Factor xa Inhibitors

ABSTRACT

Compounds of formula (I)  
                 
 
in which R 1 , n, Z, R 3  and R 4  have any of the meanings given in the specification, are inhibitors of the serine protease Factor Xa and are useful in the treatment of thrombotic disorders.

This application claims the benefit of U.S. provisional patentapplication Ser. No. 60/436,625 filed Dec. 30, 2002, the disclosure ofwhich is incorporated by reference herein.

The present invention relates to compounds useful as pharmaceuticals, topharmaceutical compositions comprising the compounds, to a process forpreparing the compounds, to intermediates useful in the preparation ofthe compounds, and to use of the compounds as pharmaceuticals.

Cardiovascular disease continues to present a major worldwide healthproblem, and is a common cause of serious illness and death.

One line of investigation being pursued by researchers in the search fornew treatments for cardiovascular disease is based upon the hypothesisthat an inhibitor of the serine protease, Factor Xa, may be useful as ananticoagulant agent in the treatment of thrombotic disease.

Inhibitors of Factor Xa are known. For example, WO 01/96303 disclosescompounds containing an aromatic group, a glycine residue bearing acyclic group, and a cyclic amine linked to the glycine residue throughan amide group.

Surprisingly, it has now been found that by replacing the amide group incompounds of WO 01/96303 with an alkylene, oxaalkylene or azaalkylenegroup, compounds may be obtained that are selective Factor Xa inhibitorsand have particularly advantageous properties.

Accordingly, the present invention provides a compound of formula (I)

in which:—

-   -   R¹ represents pyrrolidin-1-yl, piperidin-1-yl or a group of        formula        in which X represents CH or N;    -   R² represents a hydrogen atom or a (1-6C)alkyl,        (3-6C)cycloalkyl, fluoro(1-4C)alkyl, fluoro(2-4C)alkanoyl,        hydroxy(2-4C)alkyl or pyridyl group;    -   n represents 1, 2 or 3;    -   Z represents CH₂, O or NR⁵, in which R⁵ represents a hydrogen        atom or a (1-4C)alkyl group, provided that when R¹ represents        pyrrolidin-1-yl, piperidin-1-yl or a group of formula        and Z represents O or NR⁵, then n represents 2 or 3;    -   R³ represents:—    -   (i) phenyl which is unsubstituted or substituted by        methylenedioxy or by a substituent selected from halogen,        (1-4C)alkyl, hydroxy, (1-4C)alkoxy, trifluoromethyl,        difluoromethoxy, trifluoromethoxy, (1-4C)alkylthio,        (1-4C)alkylsulfinyl, (1-4C)alkylsulfonyl, carboxy,        aminocarbonyl, amino, (2-4C)alkanoylamino, aminosulfonyl,        (1-4C)alkylaminosulfonyl, nitro, phenyl, phenoxy, benzyloxy and        pyridyl;    -   (ii) pyridyl, pyrimidyl or pyridazinyl, which is unsubstituted        or substituted by a halogen atom;    -   (iii) furyl, thienyl, imidazolyl, thiazolyl, isothiazolyl,        oxazolyl, isoxazolyl, thiadiazolyl, each of which is        unsubstituted or substituted by (1-4C)alkyl or amino;    -   (iv) naphthyl, benzofuryl, benzothienyl, quinolyl or        isoquinolyl;    -   (v) (3-6C)cycloalkyl; or    -   (vi) (1-4C)alkyl, which is unsubstituted or substituted by        hydroxy, (1-4C)alkoxy, phenoxy, carboxy, aminocarbonyl,        aminosulfonyl, (1-4C)alkylthio, phenylthio, pyridylthio, amino,        (1-4C)alkylamino, di(1-4C)alkylamino, piperidin-1-yl,        morpholino, trifluoromethyl, phenyl, imidazolyl, pyridyl,        (3-6C)cycloalkyl, oxa(4-6C)cycloalkyl, or aza(4-6C)cycloalkyl        (which may bear an N-(1-4C)alkyl substituent); and    -   R⁴ is selected from        in which    -   X¹ represents a hydrogen atom, a halogen atom or an amino group;    -   X² represents a hydrogen atom, a methyl group, a chlorine atom        or a bromine atom;    -   X³ represents a hydrogen atom, a methyl group or a halogen atom;    -   X⁴ represents a chlorine atom, a methoxy group or a methyl        group; and    -   X⁵ represents a hydrogen atom, a halogen atom or a methyl group;    -   or a pharmaceutically acceptable salt thereof.

Compounds of formula (I) have been found to be potent and selectiveinhibitors of the serine protease, Factor Xa, to have good anticoagulantactivity in human plasma, to have good plasma exposure upon oraladministration to mammals, and to possess particularly advantageouspharmacological profiles of activity.

It will be appreciated that compounds of formula (I) excluded by theproviso would be expected to be chemically unstable.

It will also be appreciated that the compounds of formula (I) contain acenter of asymmetry that has the (R)-configuration when Z is O or NR⁵and the (S)-configuration when Z is CH₂. The compounds may thereforeexist and be isolated in a mixture with the corresponding (S)- or(R)-isomer respectively, such as a racemic mixture, or separately.Preferably the compounds are isolated substantially free of therespective isomers.

It will further be appreciated that the compounds of formula (I) ortheir pharmaceutically acceptable salts may be isolated in the form ofsolvates, and accordingly that any such solvate is included within thescope of the present invention.

Examples of pharmaceutically acceptable salts include hydrochloridesalts.

-   -   R¹ preferably represents a group of formula        in which X represents CH or N.    -   X preferably represents CH.    -   R² preferably represents a (1-6C)alkyl, (3-6C)cycloalkyl,        fluoro(1-4C)alkyl, fluoro(2-4C)alkanoyl, hydroxy(2-4C)alkyl or        pyridyl group.

Compounds of formula (I) in which R2 represents hydrogen have generallybeen found to exhibit lower potency as Factor Xa inhibitors than thecorresponding substituted compounds. However, as described hereinafter,they are useful as intermediates in the preparation of the substitutedcompounds.

Examples of particular values for R² are methyl, ethyl, isopropyl,cyclopropyl, cyclopentyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,trifluoroacetyl, 2-hydroxyethyl and pyrid-4-yl group.

Preferably R² represents a isopropyl, cyclopropyl, cyclopentyl orpyrid-4-yl group.

Preferably n represents 1 or 2.

More preferably n represents 1.

In one group of compounds of formula (I), Z represents CH₂.

In another group of compounds of formula (I), Z represents O. Compoundswithin this group have been found to have particularly good plasmaexposure upon oral administration to mammals.

In yet another group of compounds of formula (I), Z represents NR⁵.Compounds belonging to this group have been found to have particularlygood metabolic stability. Within this group, R⁵ preferably represent ahydrogen atom. Compounds in which R⁵ preferably represent a hydrogenatom have been found to possess particularly high potency as Factor Xainhibitors, compared with compounds in which the nitrogen atom issubstituted with R⁵.

Examples of particular values for R³ are:—

-   (i) phenyl, 2,3-methylenedioxyphenyl, 2-fluorophenyl,    4-fluorophenyl, 2-chlorophenyl, 2-methylphenyl, 2-methoxyphenyl,    2-trifluoromethylphenyl, 2-difluoromethoxyphenyl, 4-carboxyphenyl or    4-aminocarbonylphenyl;-   (ii) pyrid-2-yl or pyrid-4-yl;-   (iii) fur-2-yl, fur-3-yl, thien-2-yl, thien-3-yl, imidazol-2-yl,    thiazol-2-yl, thiazol-4-yl, 2-methylthiazol-4-yl or    2-aminothiazol-4-yl;-   (iv) naphth-1-yl, naphth-2-yl, benzofuryl, benzothienyl,    quinolin-4-yl or quinolin-8-yl;-   (v) cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or-   (vi) methyl, ethyl, propyl, isopropyl, butyl, 2-methylpropyl,    hydroxymethyl, 1-hydroxyethyl, methoxymethyl, 1-methoxyethyl,    methylthiomethyl, 2-methylthioethyl, prop-2-ylthiomethyl,    N,N-dimethylaminomethyl, phenylthiomethyl, pyrid-2-ylthiomethyl,    carboxymethyl, 2-carboxyethyl, aminocarbonylmethyl,    2-aminocarbonylethyl, morpholinomethyl, 2,2,2-trifluoroethyl,    benzyl, pyrid-2-ylmethyl, pyrid-3-ylmethyl, pyrid-4-ylmethyl,    imidazol-1-ylmethyl, imidazol-4-ylmethyl,    3-methylimidazol-4-ylmethyl, cyclohexyl-4-ylmethyl,    tetrahydropyran-4-ylmethyl, piperidin-1-ylmethyl or    1-methylpiperidin-4-ylmethyl.

Preferably R³ represents phenyl, 2-fluorophenyl or 2-chlorophenyl.

More preferably R³ represents phenyl.

X² preferably represents a hydrogen atom or a halogen atom.

More preferably X² represents a hydrogen atom or a fluorine atom.

X³ preferably represents a hydrogen atom, a chlorine atom or a methylgroup.

X⁴ preferably represents a chlorine atom.

X⁵ preferably represents a chlorine atom or a methoxy group.

X⁶ preferably represents a chlorine atom.

Examples of particular values for R⁴ are 4-chlorophenyl,4-methoxyphenyl, indol-6-yl, 3-methylindol-6-yl, 3-chloroindol-6-yl,5-chloroindol-2-yl or 6-chlorobenzo[b]thiophen-2-yl.

Preferably R⁴ is 4-methoxyphenyl, indol-6-yl or 5-chloroindol-2-yl.

Particular mention may be made of:—

-   3-Chloro-N-[(R)-1-phenyl-2-[1-(4-pyridinyl)piperidin-4-yl-methoxy]ethyl]-1H-indole-6-carboxamide;-   3-Chloro-N-{(R)-2-[(1-isopropylpiperidin-4-ylmethyl)amino]-1-phenylethyl}-1H-indole-6-carboxamide;    and pharmaceutically acceptable salts thereof.

According to another aspect, the present invention provides a processfor preparing a compound of formula (I) or a pharmaceutically acceptablesalt thereof as defined hereinabove, which comprises

-   -   (a) reacting a compound of formula (II)        or a salt thereof, with a compound of formula (III)        HOOC—R⁴  (III)        or a reactive derivative thereof;    -   (b) for a compound of formula (I) in which R² represents a        (1-6C)alkyl, (3-6C)cycloalkyl, fluoro(1-4C)alkyl,        fluoro(2-4C)alkanoyl or hydroxy(2-4C)alkyl group, reacting a        corresponding compound of formula (I) in which R² represents a        hydrogen atom, or a salt thereof, with an alkylating or        acylating agent;    -   (c) for a compound of formula (I) in which Z represents NH,        deprotecting a compound of formula    -   in which R⁶ represents an amino protecting group; or    -   (d) for a compound of formula (I) in which R² represents a        hydrogen atom, deprotecting a compound of formula (I) in which        R² represents a protecting group;    -   followed, if a pharmaceutically acceptable salt is desired, by        forming a pharmaceutically acceptable salt.

The reaction between the compound of formula (II) with the compound offormula (III) may conveniently be performed employing reagents andreaction conditions conventionally used for the formation of an amidebond. The reaction is conveniently carried out in the presence of abenzotriazole-based reagent such as 1-hydroxybenzotriazole,1-hydroxy-7-azabenzotriazole orO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate,and a carbodiimide-based dehydrating agent such asdicyclohexylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, in an inert organicsolvent such as dimethylformamide and/or methylene chloride. Thereaction is conveniently conducted at a temperature of from 0 to 50° C.,preferably at ambient temperature. If a salt of a compound of formula(II) is used, the reaction is conveniently performed in the additionalpresence of a base such as triethylamine. Other suitable reagents andsolvents are known in the art, for example an acid halide, such asp-anisoyl chloride, or an acid anhydride, in the presence of a base,such as triethylamine or pyridine.

The alkylation of a compound of formula (I) in which R² represents ahydrogen atom may be performed using a conventional alkylating agent,such as by reductive alkylation using an aldehyde or ketone as thealkylating agent, or by reaction with a compound of formulaR²-Z^(a)in which Z^(a) represents a leaving atom or group, for example achlorine or bromine atom or an organosulfonyloxy group, such astrifluoromethanesulfonyloxy.

Thus, the compound of formula (I) may be reacted with an aldehyde orketone in the presence of a reducing agent, such as sodiumcyanoborohydride or sodium triacetoxyborohydride. The reaction isconveniently performed at a temperature in the range of from 0 to 100°C. Suitable solvents include alkanols, such as methanol, halogenatedhydrocarbons, such as methylene chloride, and carboxylic acids, such asacetic acid.

The alkylation of a compound of formula (I) in which R² represents ahydrogen atom with a compound of formulaR²-Z^(a)is conveniently performed in the presence of a base, such as potassiumcarbonate. Convenient solvents include sulfoxides, such asdimethylsulfoxide and alkanols, such as ethanol. The reaction isconveniently performed at a temperature in the range of from 0 to 100°C.

The acylation of a compound of formula (I) in which R² represents ahydrogen atom may be performed using a method analogous to process step(a) as described hereinabove.

In processes (c) and (d), the protecting group represented by R⁶ and R²respectively may be any suitable amino protecting group. The protectionof amino groups is described in McOmie, Protecting Groups in OrganicChemistry, Plenum Press, NY, 1973, and Greene and Wuts, ProtectingGroups in Organic Synthesis, 2nd. Ed., John Wiley & Sons, NY, 1991.Examples of amino protecting groups include acyl groups, such as groupsof formula R⁸CO in which R⁸ represents C₁₋₆ alkoxy, aryl-C₁₋₆ alkoxy(such as phenyl-C₁₋₆ alkoxy or fluorenyl-C₁₋₆ alkoxy), or C₃₋₁₀cycloalkoxy, wherein a phenyl group may be optionally substituted, forexample by one or two of halogen, C₁-C₄ alkyl and C₁-C₄ alkoxy.

Preferred amino protecting groups include benzyloxycarbonyl (CBz),t-butoxycarbonyl (Boc) and 9-fluorenylmethoxycarbonyl (fmoc).

The compounds of formula (II) in which Z represents 0 may be prepared byreacting a compound of formula (V)

with a compound of formula (VI)R¹(CH₂)_(n)-Z^(b)  (VI)in which Z^(b) represents a leaving atom or group, such as amethanesulfonyloxy group, or a protected derivative thereof in which anyR² present in R¹ represents an amino protecting group, such ast-butoxycarbonyl, in the presence of a strong base, such as sodiumhydride.

The compounds of formula (II) in which Z represents CH₂ may be preparedby reducing an oxime compound of formula(VII)

for example using hydrogen in the presence of palladium on carbon.

The compounds of formula (VII) may be prepared by reacting a compound offormula (VIII)

with hydroxylamine hydrochloride.

The compounds of formula (II) in which Z represents NR⁵ may be preparedby deprotecting a compound of formula (IX)

in which R⁷ represents an amino protecting group, such ast-butoxycarbonyl.

The compounds of formula (IX) in which R⁵ represents hydrogen may bealkylated to afford compounds of formula (IX) in which R⁵ represents(1-4C)alkyl, or may be protected on the nitrogen with a protecting groupR⁶ to afford a compound of formula (IX) in which R⁵ represents R⁶, foruse in the preparation of compounds of formula (IV) as describedhereinafter.

The compounds of formula (IX) in which R⁵ represents hydrogen may beprepared by reducing a compound of formula(X)

The compounds of formula (X) may be prepared by coupling a protectedamino acid of formula (XI)

with an amine of formula (XII)R¹(CH₂)_(n)—NR⁵H  (XII)using a procedure analogous to process (a) described hereinabove

The compounds of formula (III) are well known.

The compounds of formula (IV) may be prepared by reacting a compound offormula (IX) in which R⁵ represents R⁶ with a compound of formula (III)or a reactive derivative thereof, as described for process step (a)hereinabove.

Certain of the intermediates described herein, for example the compoundsof formulae (II) and (IV), are believed to be novel and accordingly areprovided as further aspects of the invention.

The compounds of the invention may be administered by any convenientroute, e.g. into the gastrointestinal tract (e.g. rectally or orally),the nose, lungs, musculature or vasculature or transdermally. Thecompounds may be administered in any convenient administrative form,e.g. tablets, powders, capsules, solutions, dispersions, suspensions,syrups, sprays, suppositories, gels, emulsions, patches etc. Suchcompositions may contain components conventional in pharmaceuticalpreparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulkingagents, and further active agents. If parenteral administration isdesired, the compositions will be sterile and in a solution orsuspension form suitable for injection or infusion. Such compositionsform a further aspect of the invention.

According to another aspect, the present invention provides apharmaceutical composition, which comprises a compound of formula (I) ora pharmaceutically acceptable salt thereof, as defined hereinabove,together with a pharmaceutically acceptable diluent or carrier.

According to another aspect, the present invention provides the compoundof formula (I) or a pharmaceutically acceptable salt thereof, for use intherapy.

According to another aspect, the present invention provides the use ofthe compound of formula (I) or a pharmaceutically acceptable saltthereof, for the manufacture of a medicament for the treatment of athrombotic disorder.

According to another aspect, the present invention provides a method oftreating a thrombotic disorder in a subject requiring treatment, whichcomprises administering an effective amount of a compound of formula (I)or a pharmaceutically acceptable salt thereof.

The subject may be a human or a non-human animal, such as a non-humanmammal, for example a cat, dog, horse, cow or sheep.

The thrombotic disorder may be, for example, venous thrombosis,pulmonary embolism, arterial thrombosis, myocardial ischaemia,myocardial infarction or cerebral thrombosis. The compounds may also beused in accordance with the method of the invention in the treatment ofacute vessel closure associated with thrombolytic therapy andrestenosis, for example after transluminal coronary angioplasty orbypass grafting of the coronary or peripheral arteries, and in themaintenance of vascular access patency in long term hemodialysispatients.

The dosage of the compounds of formula (I) will depend upon the natureand severity of the condition being treated, the administration routeand the size and species of the subject. In general, quantities in therange of from 0.01 to 100 μM/kg bodyweight will be administered.

As used herein, the term “treatment” includes prophylactic use. The term“effective amount” refers to the amount of the compound of formula (I)that is effective to reduce or inhibit the development of the symptomsof the thrombotic disorder being treated.

The compound according to the invention may be administered alone or incombination with an anticoagulant having a different mode of action orwith a thrombolytic agent.

The following Examples illustrate the invention.

Abbreviations used follow IUPAC-IUB nomenclature. Additionalabbreviations are aq., aqueous; equiv, (molar) equivalent; HPLC,high-performance liquid chromatography; rpHPLC, reverse phase HPLC; SCX,strong cation exchange resin; THF, tetrahydrofuran; HOAc, acetic acid;DMSO, dimethyl sulfoxide (perdeuterated if for NMR); EtOAc, ethylacetate; EtOH, ethanol; DMF, dimethylformamide; DCM, dichloromethane;HOAT, 1-hydroxy-7-azabenzotriazole; HOBT, 1-hydroxy benzotriazole, HBTU,O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate;DCC, dicyclohexylcarbodiimide; EDCI,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; Boc,tertiary-butyloxy-carbonyl; SiO2, silica gel; ES-MS, electrospray massspectrum; TFA, trifluoroacetic acid. All solution concentrations areexpressed as % volume/% volume unless otherwise stated. Reagents wereobtained from a variety of commercial sources.

IR means an infrared spectrum was obtained. ¹H NMR means a protonmagnetic resonance spectrum was obtained.

In general in this specification, “D-” or “R-” in the name of a productindicates the product is made beginning with a chiral starting material,for example (R)-phenylglycinol or (R)-valinol; however, racemization mayhave occurred, and the enantiomeric purity may not have been determined.For clarity and consistency, in certain cases in which R³ is an alkylgroup, the compounds have been named with the alkyl group considered asubstituent, rather than as part of a chain including the carbon towhich it is attached.

HPLC Analysis: Exterra (trademark) C18 (4.6×250 mm) column. The elutionsystem is or consisted of a linear gradient from 90:10 (0.1% TFA inH₂O):(0.1% TFA in acetonitrile) to 10:90 (0.1% TFA in H₂O):(0.1% TFA inacetonitrile) over 40 min at 30° C. and a flow rate of 1 mL/min. UVDetection is performed from 220 to 400 nm using a photodiode arraydetector unless otherwise noted.

General Experimental Procedures:

The intermediate compounds and Examples may be or were preparedaccording to the following general procedures, with exceptions as noted,or as otherwise described below, or according to analogous procedures orother procedures known to one of ordinary skill in the art.

Coupling Method A:

The coupling of an amine and carboxylic acid to form an amide. Asolution of the amine (1 equiv) and carboxylic acid (1.1 equiv) in asuitable solvent (DMF and/or methylene chloride) is treated with acarbodiimide-based dehydrating agent (e.g. DCC, or EDCI)(1.0 equiv). Ingeneral, addition of a benzotriazole-based reagent (e.g., HOBT, HBTU, orHOAT)(1 equiv) improves or improved reaction yields. After completion ofthe reaction as indicated by thin-layer chromatography, the mixture ispartitioned between water and a suitable solvent (EtOAc and/or methylenechloride or 3:1 chloroform:isopropanol) and washed with 1 N NaOH, water,brine, and concentrated. The crude mixture is then purified, asindicated, or used directly in subsequent transformations.

Coupling Method B:

The coupling of an amine and acid chloride or acid anhydride to form anamide. A solution of the amine (1 equiv) in an appropiate solvent(chloroform, and/or methylene chloride) and pyridine (1-10 equiv) istreated with an acid chloride (1.1 equiv). After completion of thereaction as indicated by thin-layer chromatography, the mixture ispartitioned between a suitable solvent (EtOAc, methylene chloride,and/or chloroform) and washed with 1 N NaOH, water, brine, andconcentrated. The crude mixture is then purified, as indicated, or useddirectly in subsequent transformations.

Deprotection Method A:

A mixture of 10% palladium on carbon and the starting material in anappropriate solvent (EtOAc, EtOH, and/or HOAc) is placed under anatmosphere of hydrogen. Upon completion, the mixture is filtered and thefiltrate concentrated. The crude mixture is then purified, as indicated,or used directly in subsequent transformations.

Deprotection Method B:

A solution of the starting material in an appropriate solvent (methylenechloride and/or chloroform) is treated with anisole (5-100 equiv)followed by trifluoroacetic acid (2-100 equiv). After completion of thereaction as indicated by thin-layer chromatography, the mixture isconcentrated. The material either is partitioned between water and asuitable solvent (EtOAc, methylene chloride, and/or chloroform) andwashed with 1 N NaOH, water, brine, and concentrated, or is loaded ontoan ion-exchange resin (SCX, Varian) and eluted with methanol followed by2 N ammonia in methanol. Concentration of the later fractions affords orafforded the free base product. The crude mixture is then purified, asindicated, or used directly in subsequent transformations.

Deprotection Method C:

A solution of the starting material in HOAc and HBr is heated at 70° C.After 6-15 h, the mixture is cooled, concentrated, treated with either 5N NaOH or sodium carbonate until about pH 12, and the mixture ispartitioned between EtOAc and water. The aqueous layer is washed withEtOAc (2-3×), the organic layers are or were combined and washed withwater, brine, and concentrated. The crude mixture is then purified, asindicated, or used directly in subsequent transformations.

Deprotection Method D:

A solution of the starting material in an appropriate solvent (methylenechloride and/or chloroform) is treated with 4 N HCl in dioxane (2-100equiv). After completion of the reaction as indicated by thin-layerchromatography, the mixture is concentrated to provide a hydrochloridesalt. To obtain the free base, the material either is partitionedbetween water and a suitable solvent (EtOAc, methylene chloride, and/orchloroform) and washed with 1 N NaOH, water, brine, and concentrated, oris loaded onto an ion-exchange resin (SCX, Varian) and eluted withmethanol followed by 2 N ammonia in methanol. Concentration of the laterfractions affords or afforded the free base product. The crude mixtureis then purified, as indicated, or used directly in subsequenttransformations.

Alkylation Method A:

A solution of the starting material (1 equiv) in 5-10% HOAc in methanol(anhydrous) is treated with the indicated aldehyde or ketone (2-10equiv) followed by sodium cyanoborohydride (2-10 equiv). Aftercompletion, the mixture is concentrated and the residue either ispartitioned between a suitable solvent (EtOAc, methylene chloride,and/or chloroform) and washed with 1 N NaOH, water, brine, andconcentrated, or is directly loaded onto an ion-exchange resin (SCX,Varian) and eluted with methanol followed by 2 N ammonia in methanol.Concentration of the later fractions affords or afforded the free baseproduct. The crude mixture is then purified, as indicated, or useddirectly in subsequent transformations.

Alkylation Method B:

A solution of the starting material (1 equiv) in methylene chloride istreated with the indicated aldehyde or ketone (2-10 equiv) followed bysodium triacetoxyborohydride (2-10 equiv). After completion, the mixtureis concentrated and the residue is partitioned between a suitablesolvent (EtOAc, methylene chloride, and/or chloroform) and washed with 1N NaOH, water, brine, and concentrated. The material is dissolved in 5%HOAc in methanol and loaded onto an ion-exchange resin (SCX, Varian) andeluted with methanol followed by 2 N ammonia in methanol. Concentrationof the later fractions affords or afforded the free base product. Thecrude mixture is then purified, as indicated, or used directly insubsequent transformations.

Amino Alcohol Alkylation Method A:

To a 0.1 M solution of the starting amino alcohol in 5:1 to 10:1THF:acetonitrile is added 1.2 equivalents of sodium hydride (60%dispersion in oil). The reaction flask is heated at 80° C. for 1-2 h andis then allowed to cool to room temperature. One equivalent of4-(methane-sulfonyloxymethyl)piperidine-1-carboxylic acid tert-butylester is then added and the reaction is then heated at refluxtemperature overnight. The reaction mixture is allowed to cool to roomtemperature and a saturated solution of NaHCO₃ is added. The layer isextracted 2-3 times with a suitable solvent (3:1 chloroform:isopropanolor EtOAc), the organic layers are or were combined, dried over Na₂SO₄,filtered, and concentrated to afford a crude residue. The crude residueis then purified as indicated.

HCl Salt Formation Method A:

A compound containing a basic amine is suspended in water and is treatedwith one equivalent of aqueous HCl. The suspension is agitated orsubjected to sonication until all material is dissolved in the aqueousmedium. The aqueous material is lyophilized to afford the compound asthe hydrochloride salt.

HCl Salt Formation Method B:

A compound containing a basic amine is dissolved in a 4 N HCl/dioxanesolution at 0° C. The solution is concentrated under reduced pressure toafford the compound as the hydrochloride salt.

Preparation 1

4-[(R)-2-Amino-2-phenylethoxymethyl]piperidine-1-carboxylic acidtert-butyl ester

Using amino alcohol alkylation method A, (R)-phenyl-glycinol (4.0 g, 29mmol) afforded, after purification (SiO2: 1:1 EtOAc:Hexane to 9:1EtOAc:Hexane), 5.0 g (52%) of the title compound.

¹H NMR

ES-MS m/e 335 (m+1)

Preparation 2

4-[2-Amino-2-(2-chlorophenyl)ethoxymethyl]piperidine-1-carboxylic acidtert-butyl ester

Using amino alcohol alkylation method A, (2-chloro-phenyl)glycinol (6.6g, 39 mmol) afforded, after purification (SiO2: 100% EtOAc), 7.5 g (53%)of the title compound.

¹H. NMR

ES-MS m/e 369 (m+1)

Preparation 3

4-[2-Amino-2-(2-fluorophenyl)ethoxymethyl]piperidine-1-carboxylic acidtert-butyl ester

Using amino alcohol alkylation method A, (2-fluoro-phenyl)glycinol (1.7g, 11 mmol) afforded, after purification (SiO2: 2.5% isopropyl amine in1:1 EtOAc:hexane), 1.7 g (43%) of the title compound.

¹H NMR

ES-MS m/e 353 (m+1)

Preparation 4

4-[2-Amino-2-(4-fluorophenyl)ethoxymethyl]piperidine-1-carboxylic acidtert-butyl ester

Using amino alcohol alkylation method A, (4-fluoro-phenyl)glycinol (2.5g, 16 mmol) afforded, after purification (SiO2: 2.5% isopropyl amine in1:1 EtOAc:hexane), 2.8 g (50%) of the title compound.

¹H NMR

ES-MS m/e 353 (m+1)

Preparation 5

4-[2-Amino-2-(2-pyridinyl)ethoxymethyl]piperidine-1-carboxylic acidtert-butyl ester

Using amino alcohol alkylation method A, but adding 1.1 equivalents of4-(methanesulfonyloxymethyl)piperidine-1-carboxylic acid tert-butylester instead of 1 equivalent, (2-pyridinyl)glycinol (1.7 g, 12 mmol)afforded, after purification (SiO2: 0 to 5% 1 N ammonia/methanolsolution in DCM), 750 mg (18%) of the title compound.

¹H NMR

ES-MS m/e 336 (m+1)

Preparation 6

4-[2-Amino-2-(4-pyridinyl)ethoxymethyl]piperidine-1-carboxylic acidtert-butyl ester

Using amino alcohol alkylation method A, but adding 1.1 equivalents of4-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butyl esterinstead of 1 equivalent, (4-pyridinyl)glycinol (440 mg, 0.44 mmol)afforded, after purification (SiO2: 0 to 5% 2 N ammonia/methanolsolution in DCM), 236 mg (22%) of the title compound.

¹H NMR

ES-MS m/e 336 (m+1)

Preparation 7

4-[(2R)-2-Amino-2-(isopropyl)ethoxymethyl]piperidine-1-carboxylic acidtert-butyl ester

Using amino alcohol alkylation method A, (R)-valinol (0.84 g, 8.1 mmol)afforded, after purification (SiO2: 7:3:1 hexane:EtOAc:isopropyl amine),1.4 g (55%) of the title compound.

¹H NMR

ES-MS m/e 301 (m+1)

Preparation 8

4-[2-Amino-2-cyclopentylethoxymethyl]piperidine-1-carboxylic acidtert-butyl ester

Using amino alcohol alkylation method A, but adding 1.1 equivalents of4-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butyl esterinstead of 1 equivalent, cyclopentylglycinol (1.1 g, 8.1 mmol) afforded,after purification (SiO2: 7:3:1 hexane:EtOAc:isopropyl amine), 460 mg(16%) of the title compound.

¹H NMR

ES-MS m/e 327 (m+1)

Preparation 9

4-[(R)-2-Amino-2-(butyl)ethoxymethyl]piperidine-1-carboxylic acidtert-butyl ester

Using amino alcohol alkylation method A, but adding 1.1 equivalents of4-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butyl esterinstead of 1 equivalent, (R)-norleucinol (400 mg, 3.4 mmol) afforded,after purification (SiO2: 7:3:1 hexane:EtOAc:isopropyl amine), 195 mg(18%) of the title compound.

¹H NMR

ES-MS m/e 313 (m⁻¹)

Preparation 10

4-{(R)-2-[(3-Chloro-1H-indole-6-carbonyl)amino]-2-phenyl-ethoxymethyl}piperidine-1-carboxylicacid tert-butyl ester

Using coupling method A,4-[(R)-2-amino-2-phenylethoxy-methyl]piperidine-1-carboxylic acidtert-butyl ester (3 g, 9.0 mmol) and 3-chloroindole-6-carboxylic acid(1.7 g, 9.0 mmol) afforded the title compound as a crude residue, whichwas used without further purification.

¹H NMR

ES-MS m/e 510 (m⁻¹)

Preparation 11

4-{(R)-2-[(3-Methyl-1H-indole-6-carbonyl)amino]-2-phenyl-ethoxymethyl}piperidine-1-carboxylicacid tert-butyl ester

Using coupling method A,4-[(R)-2-amino-2-phenylethoxy-methyl)piperidine-1-carboxylic acidtert-butyl ester (1 g, 3.0 mmol) and 3-methylindole-6-carboxylic acid(0.54 g, 3.0 mmol) afforded the title compound as a crude residue, whichwas used without further purification.

¹H NMR

ES-MS m/e 492 (m+1)

Preparation 12

4-{2-[(3-Chloro-1H-indole-6-carbonyl)amino]-2-(2-chloro-phenyl)ethoxymethyl}piperidine-1-carboxylicacid tert-butyl ester

Using coupling method A,4-[2-amino-2-(2-chlorophenyl)-ethoxymethyl]piperidine-1-carboxylic acidtert-butyl ester (7.5 g, 20 mmol) and 3-chloroindole-6-carboxylic acid(3.9 g, 20 mmol) afforded, after purification (SiO2: 33% to 50% EtOAc inhexane), 8 g (73%) of the title compound.

¹H NMR

ES-MS m/e 546 (m+1)

Preparation 13

4-{2-(1H-Indole-6-carbonyl)amino-2-(2-chlorophenyl)ethoxy-methyl}piperidine-1-carboxylicacid tert-butyl ester

Using coupling method A,4-[2-amino-2-(2-chlorophenyl)-ethoxymethyl]piperidine-1-carboxylic acidtert-butyl ester (500 mg, 1.4 mmol) and indole-6-carboxylic acid (219mg, 1.4 mmol) afforded, after purification (SiO2: 33% to 50% EtOAc inhexane), 579 mg (83%) of the title compound.

¹H NMR

ES-MS m/e 512 (m+1)

Preparation 14

4-{2-(5-Chloro-1H-indole-2-carbonyl)amino-2-(2-chloro-phenyl)ethoxymethyl}piperidine-1-carboxylicacid tert-butyl ester

Using coupling method A,4-[2-amino-2-(2-chlorophenyl)-ethoxymethyl]piperidine-1-carboxylic acidtert-butyl ester (300 mg, 0.8 mmol) and 5-chloroindole-2-carboxylic acid(158 mg, 1.4 mmol) afforded, after purification (SiO2: 33% EtOAc inhexane), 407 mg (92%) of the title compound.

¹H NMR

ES-MS m/e 546 (m+1)

Preparation 15

4-{2-[(6-Chlorobenzo[b]thiophene-2-carbonyl)amino]-2-(2-chlorophenyl)ethoxymethyl}piperidine-1-carboxylicacid tert-butyl ester

Using coupling method A,4-[2-amino-2-(2-chlorophenyl)-ethoxymethyl]piperidine-1-carboxylic acidtert-butyl ester (300 mg, 0.8 mmol) and6-chlorobenzo[b]thiophene-2-carboxylic acid (172 mg, 0.8 mmol) afforded,after purification (SiO2: 50% EtOAc in hexane), 353 mg (77%) of thetitle compound.

¹H NMR

ES-MS m/e 563 (m+1)

Preparation 16

4-{2-[(3-Chloro-1H-indole-6-carbonyl)amino]-2-(2-fluoro-phenyl)ethoxymethyl}piperidine-1-carboxylicacid tert-butyl ester

Using coupling method A,4-[2-amino-2-(2-fluorophenyl)-ethoxymethyl]piperidine-1-carboxylic acidtert-butyl ester (600 mg, 1.7 mmol) and 3-chloroindole-6-carboxylic acid(367 mg, 1.9 mmol) afforded, after purification (SiO2: 10 DCM: 2 EtOAc:2 Hexane: 0 to 0.125 isopropyl amine), 800 mg (90%) of the titlecompound.

¹H NMR

ES-MS m/e 531 (m+1)

Preparation 17

4-[2-[(1H-Indole-6-carbonyl)amino]-2-(2-fluorophenyl)ethoxy-methyl)piperidine-1-carboxylicacid tert-butyl ester

Using coupling method A,4-[2-amino-2-(2-fluorophenyl)-ethoxymethyl]piperidine-1-carboxylic acidtert-butyl ester (480 mg, 1.4 mmol) and indole-6-carboxylic acid (242mg, 1.5 mmol) afforded, after purification (SiO2: 0 to 40% 2 Nammonia/methanol solution in DCM), 355 mg (53%) of the title compound.

¹H NMR

ES-MS m/e 496 (m+1)

Preparation 18

4-{2-[(3-Chloro-1H-indole-6-carbonyl)amino]-2-(4-fluoro-phenyl)ethoxymethyl}piperidine-1-carboxylicacid tert-butyl ester

Using coupling method A,4-[2-amino-2-(4-fluorophenyl)-ethoxymethyl]piperidine-1-carboxylic acidtert-butyl ester (1.1 g, 3.0 mmol) and 3-chloroindole-6-carboxylic acid(653 mg, 3.3 mmol) afforded 1.6 g (100%) of the title compound as acrude residue, which was used without further purification.

¹H NMR

ES-MS m/e 531 (m+1)

Preparation 19

4-{2-[(1H-Indole-6-carbonyl)amino]-2-(4-fluorophenyl)ethoxy-methyl}piperidine-1-carboxylicacid tert-butyl ester

Using coupling method A,4-(2-amino-2-(4-fluorophenyl)-ethoxymethyl]piperidine-1-carboxylic acidtert-butyl ester (1.0 g, 2.9 mmol) and 3-indole-6-carboxylic acid (513mg, 3.2 mmol) afforded 1.4 g (100%) of the title compound as a cruderesidue, which was used without further purification.

¹H NMR

ES-MS m/e 531 (m+1)

Preparation 20

4-{2-[(3-Chloro-1H-indole-6-carbonyl)amino]-2-(2-pyridinyl)-ethoxymethyl}piperidine-1-carboxylicacid tert-butyl ester

Using coupling method A,4-[2-amino-2-(2-pyridinyl)-ethoxymethyl]piperidine-1-carboxylic acidtert-butyl ester (730 mg, 2.2 mmol) and 3-chloroindole-6-carboxylic acid(468 mg, 2.4 mmol) afforded, after purification (SiO2: 10 DCM: 2 EtOAc:2 Hexane: 0 to 1.5 isopropyl amine), 835 mg (64%) of the title compound.

¹H NMR

ES-MS m/e 514 (m+1)

Preparation 21

4-{2-[(3-Chloro-1H-indole-6-carbonyl)amino]-2-(4-pyridinyl)-ethoxymethyl}piperidine-1-carboxylicacid tert-butyl ester

Using coupling method A,4-[2-amino-2-(4-pyridinyl)-ethoxymethyl]piperidine-1-carboxylic acidtert-butyl ester (233 mg, 0.69 mmol) and 3-chloroindole-6-carboxylicacid (149 mg, 0.76 mmol) afforded, after purification (SiO2: 10 DCM: 2EtOAc: 2 Hexane: 3 isopropyl amine), 118 mg (33%) of the title compound.

¹H NMR

ES-MS m/e 514 (m+1)

Preparation 22

4-{2-[(3-Chloro-1H-indole-6-carbonyl)amino]-2-cyclopentyl-ethoxymethyl}piperidine-1-carboxylicacid tert-butyl ester

Using coupling method A,4-(2-amino-2-cyclopentyl-ethoxymethyl)piperidine-1-carboxylic acidtert-butyl ester (460 mg, 1.4 mmol) and 3-chloroindole-6-carboxylic acid(275 mg, 1.4 mmol) afforded, after purification (SiO2: 40% EtOAc inhexane), 211 mg (30%) of the title compound.

¹H NMR

ES-MS m/e 504 (m+1)

Preparation 23

4-{(R)-2-[(3-Chloro-1H-indole-6-carbonyl)amino]-2-(butyl)-ethoxymethyl}piperidine-1-carboxylicacid tert-butyl ester

Using coupling method A,4-[(R)-2-amino-2-(butyl)-ethoxymethyl]piperidine-1-carboxylic acidtert-butyl ester (195 mg, 0.62 mmol) and 3-chloroindole-6-carboxylicacid (133 mg, 0.68 mmol) afforded, after purification (SiO2: 40% EtOAcin hexane), 90 mg (29%) of the title compound.

¹H NMR

ES-MS m/e 504 (m+1)

Preparation 24

4-[(R)-2-Benzyloxycarbonylamino-2-phenylethoxymethyl)-piperidine-1-carboxylicacid tert-butyl ester

Using coupling method B,4-[(R)-2-amino-2-phenylethoxy-methyl)piperidine-1-carboxylic acidtert-butyl ester (2 g, 6.0 mmol) and dibenzyl dicarbonate (2.1 g, 7.2mmol) afforded 3.4 g (100%) of the title compound as a crude residue,which was used without further purification.

¹H NMR

ES-MS m/e 469 (m+1)

Preparation 25

4-[(2R)-2-Benzyloxycarbonylamino-2-(isopropyl)ethoxymethyl]-piperidine-1-carboxylicacid tert-butyl ester

Using coupling method B,4-[(2R)-2-amino-2-(isopropyl)-ethoxymethyl]piperidine-1-carboxylic acidtert-butyl ester (1.3 g, 4.5 mmol) and dibenzyl dicarbonate (1.5 g, 5.3mmol) afforded 1.9 g (100%) of the title compound as a crude residue,which was used without further purification.

¹H NMR

ES-MS m/e 435 (m+1)

EXAMPLE 13-Chloro-N-[(R)-1-phenyl-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamidehydrochloride

Using deprotection method D,4-{(R)-2-[(3-chloro-1H-indole-6-carbonyl)amino]-2-phenylethoxymethyl}piperidine-1-carboxylicacid tert-butyl ester (1.7 g crude, 3.2 mmol) afforded 1.4 g (97%) ofthe title compound as a crude residue, which was used without furtherpurification.

¹H NMR

ES-MS m/e 412 (m+1)

Preparation of the Free Base

3-Chloro-N-[(R)-1-phenyl-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide

Using deprotection method B, but without addition of anisole,4-{(R)-2-[(3-chloro-1H-indole-6-carbonyl)amino]-2-phenylethoxymethyl}piperidine-1-carboxylicacid tert-butyl ester (4.6 g crude, 8.97 mmol) afforded 5 g (100%) ofthe title compound as a crude residue, which was used without furtherpurification.

¹H NMR

ES-MS m/e 412 (m+1)

Preparation 26

3-Methyl-N-[(R)-1-phenyl-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide

Using deprotection method B, but without addition of anisole,4-{(R)-2-[(3-methyl-1H-indole-6-carbonyl)amino]-2phenylethoxymethyl}piperidine-1-carboxylicacid tert-butyl ester (1.5 g crude, 3.0 mmol) afforded the titlecompound as a crude residue, which was used without furtherpurification.

¹H NMR

ES-MS m/e 392 (m+1)

Preparation 27

3-Chloro-N-[1-(2-chlorophenyl)-2-(piperidin-4-ylmethoxy)-ethyl]-1H-indole-6-carboxamide

Using deprotection method D,4-{2-[(3-chloro-1H-indole-6-carbonyl)amino]-2-(2-chlorophenyl)ethoxymethyl}piperidine-1-carboxylicacid tert-butyl ester (8 g, 14 mmol) afforded 6.1 g (94%) of the titlecompound as a crude residue, which was used without furtherpurification.

¹H NMR

ES-MS m/e 446 (m+1)

Preparation 28

N-[1-(2-Chlorophenyl)-2-(piperidin-4-ylmethoxy)ethyl]-11-indole-6-carboxamide

Using deprotection method D,4-{2-(1H-indole-6-carbonyl)amino-2-(2-chlorophenyl)ethoxymethyl}piperidine-1-carboxylicacid tert-butyl ester (270 mg, 0.53 mmol) afforded 200 mg (92%) of thetitle compound as a crude residue, which was used without furtherpurification.

¹H NMR

ES-MS m/e 412 (m+1)

Preparation 29

5-Chloro-N-[1-(2-chlorophenyl)-2-(piperidin-4-ylmethoxy)-ethyl]-1H-indole-2-carboxamide

Using deprotection method D,4-{2-(5-chloro-1H-indole-2-carbonyl)amino-2-(2-chlorophenyl)ethoxymethyl}piperidine-1-carboxylicacid tert-butyl ester (400 mg, 0.73 mmol) afforded, after SCXpurification, 326 mg (95%) of the title compound.

¹H NMR

ES-MS m/e 446 (m+1)

Preparation 30

6-Chloro-N-[1-(2-chlorophenyl)-2-(piperidin-4-ylmethoxy)-ethyl]benzo[b]thiophene-2-carboxamide

Using deprotection method D,4-{2-[(6-chlorobenzo[b]-thiophene-2-carbonyl)amino]-2-(2-chlorophenyl)ethoxymethyl)-piperidine-1-carboxylicacid tert-butyl ester (345 mg, 0.61 mmol) afforded, after SCXpurification, 260 mg (92%) of the title compound.

¹H NMR

ES-MS m/e 463 (m+1)

Preparation 31

3-Chloro-N-[1-(2-fluorophenyl)-2-(piperidin-4-ylmethoxy)-ethyl]-1H-indole-6-carboxamide

Using deprotection method D,4-{2-[(3-chloro-1H-indole-6-carbonyl)amino]-2-(2-fluorophenyl)ethoxymethyl}piperidine-1-carboxylicacid tert-butyl ester (750 mg, 1.4 mmol) afforded, after SCXpurification, 553 mg (91%) of the title compound.

¹H NMR

ES-MS m/e 430 (m+1)

Preparation 32

N-[1-(2-Fluorophenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide

Using deprotection method D,4-{2-[(1H-indole-6-carbonyl)amino]-2-(2-fluorophenyl)ethoxymethyl}piperidine-1-carboxylicacid tert-butyl ester (350 mg, 0.71 mmol) afforded, after SCXpurification, 135 mg (48%) of the title compound.

¹H NMR

ES-MS m/e 396 (m+1)

Preparation 33

3-Chloro-N-[1-(4-fluorophenyl)-2-(piperidin-4-ylmethoxy)-ethyl]-1H-indole-6-carboxamide

Using deprotection method B, but without addition of anisole,4-{2-[(3-chloro-1H-indole-6-carbonyl)amino]-2-(4-fluorophenyl)ethoxymethyl}piperidine-1-carboxylicacid tert-butyl ester (2.3 g, 4.3 mmol) afforded, after purification(SiO2: 25% isopropyl amine in ethyl acetate), 1.0 g (54%) of the titlecompound.

¹H NMR

ES-MS m/e 430 (m+1)

Preparation 34

N-[1-(4-Fluorophenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide

Using deprotection method B, but without addition of anisole,4-{2-[(1H-indole-6-carbonyl)amino]-2-(4-fluoro-phenyl)ethoxymethyl}piperidine-1-carboxylicacid tert-butyl ester (1.6 g, 3.2 mmol) afforded 1.3 g (100%) of thetitle compound as a crude residue which was used without furtherpurification.

¹H NMR ES-MS m/e 430 (m+1)

Preparation 35

3-Chloro-N-[1-(2-pyridinyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide

Using deprotection method D,4-{2-[(3-chloro-1H-indole-6-carbonyl)amino]-2-(2-pyridinyl)ethoxymethyl}piperidine-1-carboxylicacid tert-butyl ester (200 mg, 0.39 mmol) afforded 160 g (100%) of thetitle compound as a crude residue, which was used without furtherpurification.

¹H NMR

ES-MS m/e 413 (m+1)

Preparation 36

3-Chloro-N-[1-(4-pyridinyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide

Using deprotection method B, but without addition of anisole,4-(2-[(3-chloro-1H-indole-6-carbonyl)amino]-2-(4-pyridinyl)ethoxymethyl}piperidine-1-carboxylicacid tert-butyl ester (83 mg, 0.16 mmol) afforded 67 mg (100%) of thetitle compound as a crude residue, which was used without furtherpurification.

¹H NMR

ES-MS m/e 413 (m+1)

Preparation 37

3-Chloro-N-[1-cyclopentyl-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide

Using deprotection method D,4-{2-[(3-chloro-1H-indole-6-carbonyl)amino]-2-cyclopentylethoxymethyl}piperidine-1-carboxylicacid tert-butyl ester (211 mg, 0.42 mmol) afforded, after SCXpurification, 140 mg (83%) of the title compound.

¹H NMR

ES-MS m/e 402 (m-1)

Preparation 38

3-Chloro-N-[1-butyl-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide

Using deprotection method D,4-{(R)-2-[(3-chloro-1H-indole-6-carbonyl)amino]-2-butylethoxymethyl}piperidine-1-carboxylicacid tert-butyl ester (90 mg, 0.18 mmol) afforded, after SCXpurification, the title compound a's a crude residue, which was usedwithout further purification.

ES-MS m/e 397 (m+1)

Preparation 39

Benzyl N-[(R)-1-Phenyl-2-(piperidin-4-ylmethoxy)ethyl]-carbamatehydrochloride

Using deprotection method D,4-[(R)-2-benzyloxy-carbonylamino-2-phenylethoxymethyl)piperidine-1-carboxylicacid tert-butyl ester (3.7 g, 7.9 mmol) afforded 3.7 g (100%) of thetitle compound as a crude residue, which was used without furtherpurification.

¹H NMR

ES-MS m/e 369 (m+1)

Preparation 40

Benzyl N-[(R)-1-(Isopropyl)-2-(piperidin-4-ylmethoxy)ethyl]-carbamate

Using deprotection method D, crude4-[(2R)-2-benzyloxy-carbonylamino-2-(isopropyl)ethoxymethyl]piperidine-1-carboxylicacid tert-butyl ester (4.5 mmol) afforded, after SCX purification andthen further purification (SiO2: 60 to 100% EtOAc in DCM), 1.1 g (72%)of the title compound.

¹H NMR

ES-MS m/e 335 (m+1)

EXAMPLE 23-Chloro-N-[(R)-1-phenyl-2-(1-isopropylpiperidin-4-yl-methoxy)ethyl]-1H-indole-6-carboxamide

Using alkylation method A,3-chloro-N-[(R)-1-phenyl-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide(8.97 mmol) and acetone (6.6 mL, 90 mmol) afforded, after purification(SiO2: 8:2:1 hexane:EtOAc:isopropylamine), 2.2 g (54%) of the titlecompound.

¹H NMR

ES-MS m/e 454 (m+1)

EXAMPLE 2a3-Chloro-N-[(R)-1-phenyl-2-(1-isopropylpiperidin-4-yl-methoxy)ethyl]-1H-indole-6-carboxamidehydrochloride

Using alkylation method A,3-chloro-N-[(R)-1-phenyl-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide(200 mg, 0.45 mmol) and acetone (0.33 mL, 4.5 mmol) afforded, afterpurification (SiO2: 8:2:1 hexane:EtOAc isopropylamine) and conversion tothe HCl salt by general method B, 120 mg (55%) of the title compound.

¹H NMR

ES-MS m/e 454 (m+1)

EXAMPLE 33-Chloro-N-[(R)-1-phenyl-2-(1-cyclopentylpiperidin-4-yl-methoxy)ethyl]-1H-indole-6-carboxamide

Using alkylation method A,3-chloro-N-[(R)-1-phenyl-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamidehydrochloride (150 mg, 0.33 mmol) and cyclopentanone (0.5 mL, 5.7 mmol)afforded, after purification (SiO2: 8:2:1 hexane:EtOAc:isopropylamine),78 mg (49%) of the title compound.

¹H NMR

ES-MS m/e 481 (m+1)

EXAMPLE 43-Chloro-N-[(R)-1-phenyl-2-(1-methylpiperidin-4-yl-methoxy)ethyl]-1H-indole-6-carboxamide

Using alkylation method B,3-chloro-N-[(R)-1-phenyl-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamidehydrochloride (200 mg, 0.44 mmol) and paraformaldehyde (134 mg, 4.4mmol) afforded, after purification (SiO2: 2.5% isopropylamine in10:2:2:DCM:EtOAc:hexane), 80 mg (42%) of the title compound.

¹H NMR

ES-MS m/e 426 (m+1)

EXAMPLE 53-Chloro-N-[(R)-1-phenyl-2-(1-cyclopropylpiperidin-4-yl-methoxy)ethyl]-1H-indole-6-carboxamidehydrochloride

Using alkylation method A with addition of 3A molecular sieves,3-chloro-N-[(R)-1-phenyl-2-(piperidin-4-ylmethoxy)-ethyl]-1H-indole-6-carboxamidehydrochloride (200 mg, 0.44 mmol) and[(1-ethoxycyclopropyl)oxy]trimethylsilane (0.53 mL, 2.7 mmol) afforded,after purification (SiO2: 0 to 5% isopropylamine in 10:2:2:DCM:EtOAc:hexane) and after conversion to the HCl salt by general methodB, 80 mg (40%) of the title compound.

¹H NMR

ES-MS m/e 452 (m+1)

EXAMPLE 63-Chloro-N-[(R)-1-phenyl-2-[1-(4-pyridinyl)piperidin-4-yl-methoxy]ethyl]-1H-indole-6-carboxamide

To a suspension of3-chloro-N-[(R)-1-phenyl-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide(1.0 g, 2.2 mmol) in 20 mL of EtOH was added triethylamine (1.56 mL, 11mmol) and 4-chloropyridine hydrochloride (336 mg, 2.2 mmol). Heating themixture at 120° C. in a sealed tube afforded, after purification (SiO2:8:2:1 hexane:EtOAc isopropylamine), 185 mg (16%) of the title compound.

¹H NMR

ES-MS m/e 523 (m+1)

EXAMPLE 73-Methyl-N-[(R)-1-phenyl-2-(1-isopropylpiperidin-4-yl-methoxy)ethyl]-1H-indole-6-carboxamide

Using alkylation method A,3-methyl-N-[(R)-1-phenyl-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide(400 mg, 1.0 mmol) and acetone (0.75 mL, 10 mmol) afforded, afterpurification (SiO2: 8:2:1 hexane:EtOAc:isopropylamine), 197 mg (44%) ofthe title compound.

¹H NMR

ES-MS m/e 434 (m+1)

EXAMPLE 83-Chloro-N-[1-(2-chlorophenyl)-2-(1-isopropylpiperidin-4-yl-methoxy)ethyl]-1H-indole-6-carboxamidehydrochloride

Using deprotection method B,3-chloro-N-[1-(2-chloro-phenyl)-2-(1-isopropylpiperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide(128 mg, 0.26 mmol) afforded 122 mg (88%) of the title compound.

¹H NMR

ES-MS m/e 488 (m+1)

EXAMPLE 8a3-Chloro-N-[1-(2-chlorophenyl)-2-(1-isopropylpiperidin-4-yl-methoxy)ethyl]-1H-indole-6-carboxamide

Using alkylation method A,3-chloro-N-[1-(2-chloro-phenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide(200 mg, 0.41 mmol) and acetone (2.5 mL, 54 mmol) afforded, afterpurification (SiO2: 10:10:1 hexane EtOAc:isopropylamine), 132 mg (66%)of the title compound.

¹H NMR

ES-MS m/e 488 (m+1)

EXAMPLE 93-Chloro-N-[1-(2-chlorophenyl)-2-(1-methylpiperidin-4-yl-methoxy)ethyl]-1H-indole-6-carboxamide

Using alkylation method B,3-chloro-N-[1-(2-chloro-phenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide(300 mg, 0.67 mmol) and paraformaldehyde (201 mg, 6.7 mmol) afforded,after purification (SiO2: 10:10:1 hexane:EtOAc:isopropylamine), 175 mg(57%) of the title compound.

¹H NMR

ES-MS m/e 461 (m+1)

EXAMPLE 103-Chloro-N-[1-(2-chlorophenyl)-2-(1-ethylpiperidin-4-yl-methoxy)ethyl]-1H-indole-6-carboxamide

Using alkylation method A,3-chloro-N-[1-(2-chloro-phenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide(600 mg, 1.3 mmol) and acetaldehyde (0.4 mL, 6.7 mmol) afforded, afterpurification (SiO2: 10:10:1 hexane EtOAc:isopropylamine) andrecrystallization (acetonitrile), 275 mg (43%) of the title compound.

¹H NMR

ES-MS m/e 475 (m+1)

EXAMPLE 113-Chloro-N-[1-(2-chlorophenyl)-2-[1-(2-fluoroethyl)-piperidin-4-ylmethoxy]ethyl]-1H-indole-6-carboxamide

To a solution of3-chloro-N-[1-(2-chlorophenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide(600 mg, 1.3 mmol) in 6 mL of DMSO was added potassium carbonate (716mg, 5.2 mmol) and 2-bromo-1-fluoroethane (0.10 mL, 1.1 mmol). Thereaction was allowed to stir at room temperature overnight after whichtime water was added and the resulting precipitate was isolated byfiltration. Purification of the filtrate (SiO2: EtOAc) provided 178 mg(28%) of the title compound.

¹H NMR

ES-MS m/e 493 (m+1)

EXAMPLE 123-Chloro-N-[1-(2-chlorophenyl)-2-[1-(2,2,2-trifluoroacetyl)-piperidin-4-ylmethoxy]ethyl]-1H-indole-6-carboxamide

To a solution of3-chloro-N-[1-(2-chlorophenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide(600 mg, 1.3 mmol) in 5 mL of methanol was added triethylamine (0.37 mL,2.7 mmol) and trifluoroacetic acid ethyl ester (0.20 mL, 2.7 mmol). Thereaction was allowed to stir at room temperature overnight after whichtime water was added and the resulting precipitate was isolated byfiltration. Purification of the filtrate (SiO2: 10:2:0.5 DCM:hexaneisopropylamine) provided 297 mg (41%) of the title compound.

¹H NMR

ES-MS m/e 543 (m+1)

EXAMPLE 133-Chloro-N-[1-(2-chlorophenyl)-2-[1-(2,2,2-trifluoroethyl)-piperidin-4-ylmethoxy]ethyl]-1H-indole-6-carboxamide

To a solution of3-chloro-N-[1-(2-chlorophenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide(700 mg, 1.6 mmol) in 5 mL of DMSO was added potassium carbonate (1.0 g,7.9 mmol) and 2,2,2-trifluoroethyl trifluoromethane-sulfonate (364 mg,1.6 mmol). The reaction was allowed to stir at room temperatureovernight after which time water was added and the resulting precipitatewas isolated by filtration. Purification of the filtrate (SiO2: 30%EtOAc in hexane) provided 250 mg (30%) of the title compound.

¹H NMR

ES-MS m/e 529 (m+1)

EXAMPLE 143-Chloro-N-[1-(2-chlorophenyl)-2-[1-(2-hydroxyethyl)-piperidin-4-ylmethoxy]ethyl]-1H-indole-6-carboxamide

To a solution of3-chloro-N-[1-(2-chlorophenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide(200 mg, 0.45 mmol) in 5 mL of EtOH was added potassium carbonate (247mg, 1.8 mmol), potassium iodide (224 mg, 1.4 mmol) and 2-chloroethanol(0.09 mL, 1.4 mmol). The reaction was allowed to stir at roomtemperature overnight after which time water was added and the resultingprecipitate was isolated by filtration. Purification of the filtrate(SiO2: 10:0.5 EtOAc:isopropylamine) provided 70 mg (32%) of the titlecompound.

¹H NMR

ES-MS m/e 491 (m+1)

EXAMPLE 155-Chloro-N-[1-(2-chlorophenyl)-2-(1-isopropylpiperidin-4-yl-methoxy)ethyl]-1H-indole-2-carboxamide

Using alkylation method A,5-chloro-N-[1-(2-chloro-phenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-2-carboxamide(320 mg, 0.72 mmol) and acetone (2.0 mL, 27 mmol) afforded, afterpurification (SiO2: 0 to 2.5% isopropylamine in 1:1 hexane:EtOAc) andrecrystallization (acetonitrile), 185 mg (53%) of the title compound.

¹H NMR

ES-MS m/e 488 (m+1)

EXAMPLE 166-Chloro-N-[1-(2-chlorophenyl)-2-(1-isopropylpiperidin-4-yl-methoxy)ethyl]benzo[b]thiophene-2-carboxamide

Using alkylation method A,6-chloro-N-[1-(2-chloro-phenyl)-2-(piperidin-4-ylmethoxy)ethyl]benzo[b]thiophene-2-carboxamide(255 mg, 0.55 mmol) and acetone (2.0 mL, 27 mmol) afforded, afterpurification (SiO2: 4:4:1 hexane EtOAc:isopropylamine), 150 mg (54%) ofthe title compound.

¹H NMR

ES-MS m/e 505 (m+1)

EXAMPLE 17N-[1-(2-Chlorophenyl)-2-(1-isopropylpiperidin-4-ylmethoxy)-ethyl]-1H-indole-6-carboxamide

Using alkylation method A,N-[1-(2-chlorophenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide(195 mg, 0.47 mmol) and acetone (2.0 mL, 27 mmol) afforded, afterpurification (SiO2: 0 to 2.5% isopropylamine in 1:1 hexane:EtOAc), 120mg (60%) of the title compound.

¹H NMR

ES-MS m/e 454 (m+1)

EXAMPLE 183-Chloro-N-[1-(2-fluorophenyl)-2-(1-isopropylpiperidin-4-yl-methoxy)ethyl]-1H-indole-6-carboxamide

Using alkylation method A,3-chloro-N-[1-(2-fluoro-phenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide(303 mg, 0.71 mmol) and acetone (2 mL, 27 mmol) afforded 260 mg (78%) ofthe title compound.

¹H NMR

ES-MS m/e 472 (m+1)

EXAMPLE 193-Chloro-N-[1-(2-fluorophenyl)-2-(1-methylpiperidin-4-yl-methoxy)ethyl]-1H-indole-6-carboxamide

Using alkylation method B,3-chloro-N-[1-(2-fluoro-phenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide(250 mg, 0.58 mmol) and paraformaldehyde (174 mg, 5.8 mmol) afforded,after purification (SiO2: 10:2:2:1 DCM:EtOAc:hexane:isopropylamine), 160mg (63%) of the title compound.

¹H NMR

ES-MS m/e 445 (m+1)

EXAMPLE 20N-[1-(2-Fluorophenyl)-2-(1-isopropylpiperidin-4-ylmethoxy)-ethyl]-1H-indole-6-carboxamide

Using alkylation method A,N-[1-(2-fluorophenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide(135 mg, 0.34 mmol) and acetone (1 mL, 14 mmol) afforded, afterpurification (SiO2: 10:2:2:1 DCM:EtOAc:hexane isopropylamine), 90 mg(60%) of the title compound.

¹H NMR

ES-MS m/e 438 (m+1)

EXAMPLE 213-Chloro-N-[1-(4-fluorophenyl)-2-(1-isopropylpiperidin-4-yl-methoxy)ethyl]-1H-indole-6-carboxamide

Using alkylation method A,3-chloro-N-[1-(4-fluoro-phenyl)-2-(piperidin-4-ylmethoxy)ethyl)-1H-indole-6-carboxamide(600 mg, 1.4 mmol) and acetone (10 mL, 135 mmol) afforded, aftertrituration (acetonitrile), 500 mg (76%) of the title compound.

¹H NMR

ES-MS m/e 472 (m+1)

EXAMPLE 223-Chloro-N-[1-(4-fluorophenyl)-2-(1-methylpiperidin-4-yl-methoxy)ethyl]-1H-indole-6-carboxamide

Using alkylation method B,3-chloro-N-[1-(4-fluoro-phenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide(373 mg, 0.87 mmol) and paraformaldehyde (520 mg, 17 mmol) afforded,after purification (SiO2: 8:2:1 hexane:EtOAc:isopropylamine), 115 mg(30%) of the title compound.

¹H NMR

ES-MS m/e 444 (m+1)

EXAMPLE 23N-[1-(4-Fluorophenyl)-2-(1-isopropylpiperidin-4-ylmethoxy)-ethyl]-1H-indole-6-carboxamide

Using alkylation method A,N-[1-(4-fluorophenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide(900 mg, 2.3 mmol) and acetone (25 mL, 340 mmol) afforded, afterpurification (SiO2: 8:2:1 hexane:EtOAc:isopropylamine), 45 mg (5%) ofthe title compound.

¹H NMR

ES-MS m/e 438 (m+1)

EXAMPLE 243-Chloro-N-[1-(2-pyridinyl)-2-(1-isopropylpiperidin-4-yl-methoxy)ethyl]-1H-indole-6-carboxamide

Using alkylation method A,3-chloro-N-[1-(2-pyridinyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide(170 mg, 0.41 mmol) and acetone (1.2 mL, 16.8 mmol) afforded 130 mg(70%) of the title compound.

¹H NMR

ES-MS m/e 456 (m+1)

EXAMPLE 24a3-Chloro-N-[1-(2-pyridinyl)-2-(1-isopropylpiperidin-4-yl-methoxy)ethyl]-1H-indole-6-carboxamidehydrochloride

Using deprotection method A,3-chloro-N-[1-(2-pyridinyl)-2-(1-isopropylpiperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide(105 mg, 0.25 mmol) and acetone (1.2 mL, 16.8 mmol) afforded 110 mg(96%) of the title compound.

¹H NMR

ES-MS m/e 456 (m+1)

EXAMPLE 253-Chloro-N-11-(2-pyridinyl)-2-(1-methylpiperidin-4-yl-methoxy)ethyl]-1H-indole-6-carboxamide

Using alkylation method B,3-chloro-N-[1-(2-pyridinyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide(30 mg, 0.07 mmol) and paraformaldehyde (15 mg, 0.12 mmol) afforded,after purification (SiO2: 10% isopropylamine in DCM), 20 mg (65%) of thetitle compound.

¹H NMR

ES-MS m/e 427 (m+1)

EXAMPLE 263-Chloro-N-[1-(4-pyridinyl)-2-(1-isopropylpiperidin-4-yl-methoxy)ethyl]-1H-indole-6-carboxamide

Using alkylation method A,3-chloro-N-[1-(4-pyridinyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide(67 mg, 0.16 mmol) and acetone (2 mL, 27 mmol) afforded 35 mg (47%) ofthe title compound.

¹H NMR

ES-MS m/e 455 (m+1)

EXAMPLE 273-Chloro-N-[1-cyclopentyl-2-(1-isopropylpiperidin-4-yl-methoxy)ethyl]-1H-indole-6-carboxamide

Using alkylation method A,3-chloro-N-[1-cyclopentyl-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide(140 mg, 0.35 mmol) and acetone (0.25 mL, 3.5 mmol) afforded, after SCXpurification, 67 g (44%) of the title compound.

¹H NMR

ES-MS m/e 444 (m−1)

EXAMPLE 283-Chloro-N-[1-butyl-2-(1-isopropylpiperidin-4-ylmethoxy)-ethyl]-1H-indole-6-carboxamide

Using alkylation method A,3-chloro-N-[1-butyl-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide(0.18 mmol) and acetone (1 mL, 14 mmol) afforded, after SCXpurification, 60 mg (70%) of the title compound.

¹H NMR

ES-MS m/e 435 (m+1)

Preparation 41

BenzylN-[(R)-2-(1-Isopropylpiperidin-4-ylmethoxy)-1-phenyl-ethyl]carbamate

Using alkylation method A, benzylN-[(R)-1-phenyl-2-(piperidin-4-ylmethoxy)ethyl]carbamate hydrochloride(3.7 g, 0.91 mmol) and acetone (2.3 g, 40 mmol) afforded, afterpurification (SiO2: 8:2:1 hexane:EtOAc:isopropylamine), 1.1 g (29%) ofthe title compound.

¹H NMR

ES-MS m/e 411 (m+1)

Preparation 42

BenzylN-[(R)-1-(Isopropyl)-2-(1-isopropylpiperidin-4-yl-methoxy)ethyl]carbamate

Using alkylation method A, benzylN-[(R)-1-(isopropyl)-2-(piperidin-4-ylmethoxy)ethyl]carbamate (1.1 g,3.2 mmol) and acetone (5 mL, 68 mmol) afforded 1.1 g (92%) of the titlecompound.

¹H NMR

ES-MS m/e 377(m+1)

Preparation 43

(R)-2-(1-Isopropylpiperidin-4-ylmethoxy)-1-phenylethylamine

Using deprotection method C, keeping the reaction at room temperature,benzylN-[(R)-2-(1-isopropylpiperidin-4-ylmethoxy)-1-phenylethyl]carbamate (1.5g, 3.7 mmol) afforded 725 mg (72%) of the title compound.

¹H NMR

ES-MS m/e 277 (m+1)

Preparation 44

(R)-1-(Isopropyl)-2-(1-isopropylpiperidin-4-ylmethoxy)-ethylamine

Using deprotection method A, benzylN-[(R)-1-(iso-propyl)-2-(1-isopropylpiperidin-4-ylmethoxy)ethyl]carbamate(1.1 g, 3.0 mmol) afforded 541 mg (75%) of the title compound.

¹H NMR

ES-MS m/e 243 (m+1)

EXAMPLE 29N-[(R)-2-(1-Isopropylpiperidine-4-ylmethoxy)-1-phenylethyl]-4-methoxybenzamidehydrochloride

Using coupling method B,(R)-2-(1-isopropylpiperidin-4-ylmethoxy)-1-phenylethylamine (150 mg,0.54 mmol) and 4-methoxybenzoyl chloride (0.12 mL, 1.0 mmol) afforded,after purification (SiO2: 4:2:1 DCM:EtOAc:isopropyl-amine) andconversion to the HCl salt by general method A, 205 mg (91%) of thetitle compound.

¹H NMR

ES-MS m/e 411 (m+1)

EXAMPLE 304-Chloro-N-[(R)-2-(1-isopropylpiperidine-4-ylmethoxy)-1-phenylethyl]benzamidehydrochloride

Using coupling method B,(R)-2-(1-isopropylpiperidin-4-ylmethoxy)-1-phenylethylamine (150 mg,0.54 mmol) and 4-chlorobenzoyl chloride (0.14 mL, 1.1 mmol) afforded,after purification (SiO2: 4:2:1 DCM:EtOAc:isopropylamine) and conversionto the HCl salt by general method A, 205 mg (87%) of the title compound.

¹H NMR

ES-MS m/e 415 (m+1)

EXAMPLE 31N-[(R)-2-(1-Isopropylpiperidine-4-ylmethoxy)-1-phenylethyl]-1H-indole-6-carboxamidehydrochloride

Using coupling method A,(R)-2-(1-isopropylpiperidin-4-ylmethoxy)-1-phenylethylamine (200 mg,0.73 mmol) and indole-6-carboxylic acid (117 mg, 0.73 mmol) afforded,after purification (SiO2: 4:2:1 DCM:EtOAc:isopropylamine) and conversionto the HCl salt by general method A, 270 mg (91%) of the title compound.

¹H NMR

ES-MS m/e 420 (m+1)

EXAMPLE 325-Chloro-N-[(R)-2-(1-isopropylpiperidine-4-ylmethoxy)-1-phenylethyl]-1H-indole-2-carboxamidehydrochloride

Using coupling method A,(R)-2-(1-isopropylpiperidin-4-ylmethoxy)-1-phenylethylamine (200 mg,0.73 mmol) and 5-chloroindole-2-carboxylic acid (142 mg, 0.75 mmol)afforded, after purification (SiO2: 4:2:1 DCM:EtOAc isopropylamine) andconversion to the HCl salt by general method A, 320 mg (92%) of thetitle compound.

¹H NMR

ES-MS m/e 454 (m+1)

EXAMPLE 333-Chloro-N-[(R)-1-(Isopropyl)-2-(1-isopropylpiperidine-4-yl-methoxy)ethyl]-1H-indole-6-carboxamidehydrochloride

Using coupling method A,(R)-1-(isopropyl)-2-(1-iso-propylpiperidin-4-ylmethoxy)ethylamine (135mg, 0.56 mmol) and 3-chloroindole-6-carboxylic acid (109 mg, 0.56 mmol)afforded, after purification (SiO2: 4:2:1 DCM:EtOAc:isopropylamine) andconversion to the HCl salt by general method A, 167 mg (66%) of thetitle compound.

¹H NMR

ES-MS m/e 420 (m+1)

EXAMPLE 343-Chloro-N-[(R)-1-phenyl-2-[2-(piperidin-4-yl)ethoxy]ethyl]-1H-indole-6-carboxamidehydrochloride

Using deprotection method D,4-[2-{(R)-2-[(3-chloro-1H-indole-6-carbonyl)amino]-2-phenylethoxy}ethyl]piperidine-1-carboxylicacid tert-butyl ester (474 mg, 0.9 mmol) afforded 394 mg (98%) of thetitle compound.

¹H NMR

ES-MS m/e 426 (m+1)

The starting material was prepared as described in Preparations 45 and46 below.

Preparation 45

4-[2-[(R)-2-Amino-2-phenylethoxy]ethyl]piperidine-1-carboxylic acidtert-butyl ester

Using amino alkylation method A, substituting4-(2-methanesulfonyloxyethyl)piperidine-1-carboxylic acid tert-butylester for 4-(methanesulfonyloxymethyl)piperidine-1-carboxylic acidtert-butyl ester, (R)-phenylglycinol (2.0 g, 14.6 mmol) afforded, afterpurification (SiO2: 50 to 100% EtOAc in hexane, 2.5 g (49%) of the titlecompound.

¹H NMR

ES-MS m/e 349 (m+1)

Preparation 46

4-[2-{(R)-2-[(3-Chloro-1H-indole-6-carbonyl)amino]-2-phenyl-ethoxy}ethyl]piperidine-1-carboxylicacid tert-butyl ester

Using coupling method A, 4-[2-[(R)-2-amino-2-phenyl-ethoxy]3ethyl]piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.4 mmol)and 3-chloroindole-6-carboxylic acid (280 mg, 1.4 mmol) afforded, afterpurification (SiO2: 50% EtOAc in hexane), 474 mg (63%) of the titlecompound.

¹H NMR

ES-MS m/e 526 (m+1)

EXAMPLE 353-Chloro-N-[(R)-1-phenyl-2-[2-(1-methylpiperidin-4-yl)-ethoxy]ethyl]-1H-indole-6-carboxamidehydrochloride

Using alkylation method B,3-chloro-N-[(R)-1-phenyl-2-[2-(piperidin-4-yl)ethoxy]ethyl]-1H-indole-6-carboxamidehydrochloride (300 mg, 0.65 mmol) and paraformaldehyde (195 mg, 6.5mmol) afforded 213 mg (75%) of the title compound.

¹H NMR

ES-MS m/e 441 (m+1)

EXAMPLE 363-Chloro-N-[(R)-1-phenyl-2-[3-(piperidin-1-yl)propoxy]-ethyl]-1H-indole-6-carboxamide

Using coupling method A,(R)-1-phenyl-2-[3-(piperidin-1-yl)propoxy]ethylamine (218 mg, 0.83 mmol)and 3-chloro-indole-6-carboxylic acid (179 mg, 0.91 mmol) afforded,after purification (SiO2: 50% EtOAc in hexane), 115 mg (32%) of thetitle compound.

¹H NMR

ES-MS m/e 440 (m+1)

The starting material was prepared as described in Preparation 47 below.

Preparation 47

(R)-1-Phenyl-2-[3-(piperidin-1-yl)propoxy]ethylamine

Using amino alcohol alkylation method A, substituting1-(3-chloropropyl)piperidine hydrochloride for4-(methane-sulfonyloxymethyl)piperidine-1-carboxylic acid tert-butylester, (R)-phenylglycinol (400 mg, 2.9 mmol) afforded, afterpurification (SiO2: 8:2:1 hexane:EtOAc:isopropylamine), 220 mg (29%) ofthe title compound.

¹H NMR

ES-MS m/e 263 (m+1)

EXAMPLE 373-Chloro-N-[4-(1-isopropylpiperidin-4-yl)-1-phenylbutyl]-1H-indole-6-carboxamide

Using coupling method A, crude4-(1-isopropylpiperidin-4-yl)-1-phenylbutylamine hydrochloride (0.70mmol) and 3-chloroindole-6-carboxylic acid (162 mg, 0.83 mmol) afforded,after purification (SiO2: 10:10:1 hexane:EtOAc isopropylamine), 66 mg(13%) of the title compound.

¹H NMR

ES-MS m/e 452 (m+1)

The starting material was prepared as described in Preparations 48 to 53below.

Preparation 48

1-Phenyl-4-(pyridin-4-yl)butan-1-one oxime

To a solution of 1-phenyl-4-(pyridin-4-yl)butan-1-one (2.0 g, 8.7 mmol)in 20 mL of EtOH was added hydroxylamine hydrochloride (0.73 g, 10 mmol)and sodium acetate (1.4 g, 17 mmol). The reaction flask was heated at80° C. for 4 h and was then cooled to room temperature. Addition ofwater and filtration of the resultant precipitate afforded 2.0 g (89%)of the title compound.

¹H NMR

NMR

ES-MS m/e 241 (m+1)

Preparation 49

1-Phenyl-4-(pyridin-4-yl)butylamine

Using deprotection method A under 4.1 bar (60 psig) of hydrogen,1-phenyl-4-(pyridin-4-yl)butan-1-one oxime (1.6 g, 6.5 mmol) afforded1.3 g (87%) of the title compound.

¹H NMR

ES-MS m/e 227 (m+1)

Preparation 50

N-[1-Phenyl-4-(pyridin-4-yl)-butyl]carbamic acid tert-butyl ester

Using coupling method B, but substituting triethylamine for pyridine andusing THF as solvent, 1-phenyl-4-(pyridin-4-yl)butylamine (1.0 g, 4.5mmol) and di-tert-butyl dicarbonate (1.5 g, 6.8 mmol) afforded 1.2 g(82%) of the title compound as a crude residue which was used withoutfurther purification.

¹H NMR

ES-MS m/e 227 (m+1)

Preparation 51

N-[1-Phenyl-4-(piperidine-4-yl)butyl]carbamic acid tert-butyl ester

Agitating N-[1-phenyl-4-(pyridin-4-yl)butyl]carbamic acid tert-butylester (230 mg, 0.70 mmol) and a catalytic amount of platinum oxide in 25mL of acetic acid under an atmosphere of hydrogen at 4.1 bar (60 psig)afforded, after filtration through diatomaceous earth and removal ofsolvent under reduced pressure, the title compound as a crude residuethat was used without further purification.

¹H NMR

ES-MS m/e 333 (m+1)

Preparation 52

N-[4-(1-Isopropylpiperidin-4-yl)-1-phenylbutyl]carbamic acid tert-butylester

Using alkylation method A, crudeN-[1-phenyl-4-(piperidine-4-yl)butyl]carbamic acid tert-butyl ester(0.70 mmol) and acetone (1.5 mL, 20 mmol) afforded the title compound asa crude residue that was used without further purification.

¹H NMR

ES-MS m/e 375 (m+1)

Preparation 53

4-(1-Isopropylpiperidin-4-yl)-1-phenylbutylamine hydrochloride

Using deprotection method D, crudeN-[4-(1-isopropyl-piperidin-4-yl)-1-phenylbutyl]carbamic acid tert-butylester (0.70 mmol) afforded 200 mg of the title compound as a cruderesidue that was used without further purification.

¹H NMR

ES-MS m/e 275 (m+1)

EXAMPLE 383-Chloro-N-[4-(4-isopropylpiperazin-1-yl)-1-phenylbutyl]-1H-indole-6-carboxamide

Using coupling method A, crude4-(4-isopropylpiperazin-1-yl)-1-phenylbutylamine (530 mg, 1.9 mmol) and3-chloro-indole-6-carboxylic acid (376 mg, 1.9 mmol) afforded, afterpurification (SiO2: 10:10:1 hexane:EtOAc:isopropyl-amine), 184 mg (21%)of the title compound.

¹H NMR

ES-MS m/e 454 (m+1)

The starting material was prepared as described in Preparations 54 to 56below.

Preparation 54

4-Hydroximino-4-phenylbutyric acid

To a solution of 4-oxo-4-phenylbutyric acid (1.0 g, 5.3 mmol) in 50 mLof EtOH was added hydroxylamine hydrochloride (742 mg, 11 mmol) andsodium acetate (1.8 g, 21 mmol). The reaction flask was heated at 80° C.for 4 h and was then cooled to room temperature. Addition of water andfiltration of the resultant precipitate afforded, afterrecrystallization (10:1 chloroform:hexane), 620 mg (60%) of the titlecompound.

¹H NMR

ES-MS m/e 192 (m-1)

Preparation 55

1-(4-Isopropylpiperazin-1-yl)-4-phenylbutane-1,4-dione 4-oxime

Using coupling method A, 4-hydroximino-4-phenylbutyric acid (500 mg, 2.6mmol) and 1-isopropylpiperazine dihydrochloride (521 mg, 2.6 mmol)afforded, after purification (SiO2: 10% isopropylamine in EtOAc), 730 mg(89%) of the title compound.

¹H NMR

Preparation 56

4-(4-Isopropylpiperazin-1-yl)-1-phenyl-butylamine

To a solution of 1-(4-isopropylpiperazin-1-yl)-4-phenylbutane-1,4-dione4-oxime (625 mg, 2.0 mmol) in 10 mL of THF was slowly added lithiumaluminum hydride (250 mg, 6.6 mmol). The reaction flask was heated at70° C. for 4 h after which time the flask was cooled to 0 C and thereaction was quenched by slow addition of water and 1 N sodiumhydroxide. The biphasic mixture was filtered through a pad ofdiatomaceous earth, and the filtered solution was concentrated todryness to afford 536 mg (98%) of the title compound as a crude residuethat was used without further purification.

¹H NMR

ES-MS m/e 276 (m+1)

EXAMPLE 39 3-Chloro-N-{(R)-2-[(1-isopropylpiperidin-4-ylmethyl)-(methyl)amino]-1-phenylethyl}-1H-indole-6-carboxamide

Using coupling method A, crude(R)-N²-(1-isopropyl-piperidin-4-ylmethyl)-N²-methyl-1-phenylethane-1,2-diaminedihydrochloride (500 mg, 1.4 mmol) and 3-chloroindole-6-carboxylic acid(325 mg, 1.7 mmol) afforded, after purification (SiO2: 0 to 30%isopropylamine in 1:1 hexane EtOAc), 115 mg (18%) of the title compound.

¹H NMR

ES-MS m/e 467 (m+1)

The starting material was prepared as described in Preparations 57 to 60below.

Preparation 57

N-[(R)-2-[(1-Isopropylpiperidin-4-ylmethyl)amino]-1-phenyl-2-oxoethyl]carbamicacid tert-butyl ester

Using coupling method A, N-Boc-(R)-phenylglycine (3.6 g, 14.5 mmol) and1-isopropylpiperidin-4-ylmethylamine dihydrochloride (3.3 g, 14.5 mmol)afforded, after purification (SiO2: 0 to 30% isopropylamine in 1:1hexane EtOAc), 5.3 g (94%) of the title compound.

¹H NMR

ES-MS m/e 390 (m+1)

Preparation 58

N-[(R)-2-[(1-Isopropylpiperidin-4-ylmethyl)amino]-1-phenyl-ethyl]carbamicacid tert-butyl ester

To a solution of N-[(R)-2-[(1-isopropylpiperidin-4-yl-methyl)amino]-1-phenyl-2-oxoethyl]carbamic acid tert-butyl ester (1.0 g, 2.6mmol) in 15 mL of THF was added 65 wt % sodiumbis(2-methoxyethoxy)aluminum hydride in toluene (2.4 mL, 7.7 mmol). Thereaction mixture was heated at reflux for 3 h after which time themixture was cooled to 0° C. and the reaction was quenched by the slowaddition of a saturated solution of Rochelle's salt. The product wasextracted into EtOAc; and the combined extracts were dried over sodiumsulfate, filtered, and concentrated to afford, after purification (SiO2:0 to 30% isopropylamine in 1:1 hexane:EtOAc), 0.9 g (94%) of the titlecompound.

¹H NMR

ES-MS m/e 376 (m+1)

Preparation 59

N-[(R)-2-[(1-Isopropylpiperidin-4-ylmethyl)(methyl)amino]-1-phenylethyl]carbanicacid tert-butyl ester

Using alkylation method B,N-[(R)-2-[(1-isopropyl-piperidin-4-ylmethyl)amino)-1-phenylethyl]carbamicacid tert-butyl ester (511 mg, 1.4 mmol) and paraformaldehyde (816 mg,27 mmol) afforded 522 mg (98%) of the title compound as a crude residuethat was used without further purification.

¹H NMR

ES-MS m/e 390 (m+1)

Preparation 60

(R)-N²-(1-Isopropylpiperidin-4-ylmethyl)-N²-methyl-1-phenyl-ethane-1,2-diaminehydrochloride

Using deprotection method D, crudeN-[(R)-2-[(1-iso-propylpiperidin-4-ylmethyl)(methyl)amino]-1-phenylethyl]-carbamicacid tert-butyl ester (522 mg, 1.3 mmol) afforded 600 mg of the titlecompound as a crude residue that was used without further purification.

¹H NMR

ES-MS m/e 290 (m+1)

EXAMPLE 403-Chloro-N-{(R)-2-[(1-isopropylpiperidin-4-ylmethyl)amino]-1-phenylethyl}-1H-indole-6-carboxamide

A solution ofN-[(R)-2-(3-chloro-1H-indole-6-carbonyl)-amino-2-phenylethyl]-N-(1-isopropylpiperidin-4-ylmethyl)-carbamicacid 9H-fluoren-9-ylmethyl ester (111 mg, 0.16 mmol) and piperidine(0.08 mL, 0.82 mmol) in 5 mL of DCM was stirred at room temperature for2 h. Concentration of the reaction mixture afforded, after purification(SiO2: 0 to 30% isopropylamine in 1:1 hexane:EtOAc), 18 mg (23%) of thetitle compound.

¹H NMR

ES-MS m/e 453 (m+1)

The starting material was prepared as describe din Preparations 61 to 63below.

Preparation 61

N-[(R)-2-[(9H-Fluoren-9-ylmethoxycarbonyl)(1-isopropyl-piperidin-4-ylmethyl)amino]-1-phenylethyl]carbamicacid tert-butyl ester

Using coupling method B,N-[(R)-2-[(1-isopropylpiperidin-4-ylmethyl)amino]-1-phenylethyl]carbamicacid tert-butyl ester (1.1 g, 2.8 mmol) and 9-fluorenylmethylN-succinimidyl carbonate (Fmoc-OSu, 962 mg, 2.9 mmol) afforded 1.9 g ofthe title compound as a crude residue, that was used without furtherpurification.

¹H NMR

ES-MS m/e 598 (m+1)

Preparation 62

N-(R)-2-Amino-2-phenylethyl]-N-(1-isopropylpiperidin-4-yl-methyl)carbamicacid 9H-fluoren-9-ylmethyl ester

Using deprotection method D, crudeN-[(R)-2-[(9H-fluoren-9-ylmethoxycarbonyl)(1-isopropylpiperidin-4-yl-methyl)amino]-1-phenylethyl]carbamicacid tert-butyl ester (1.7 g, 2.8 mmol) afforded 1.0 g (71%) of crudeproduct, that was used without further purification.

¹H NMR

ES-MS m/e 499 (m+1)

Preparation 63

N-[(R)-2-(3-Chloro-1H-indole-6-carbonyl)amino-2-phenyl-ethyl]-N-(1-isopropylpiperidin-4-ylmethyl)carbamicacid 9H-fluoren-9-ylmethyl ester

Using coupling method A, crudeN-[(R)-2-amino-2-phenyl-ethyl]-N-(1-isopropylpiperidin-4-ylmethyl)carbamicacid 9H-fluoren-9-ylmethyl ester (980 mg, 2.0 mmol) and3-chloro-indole-6-carboxylic acid (462 mg, 2.4 mmol) afforded, afterpurification (SiO2: 0 to 30% isopropylamine in 1:1 hexane EtOAc), 300 mg(23%) of the title compound.

¹H NMR

ES-MS m/e 675 (m+1)

Assay Protocols

Enzyme Inhibition Assays:

The ability of a test compound to inhibit factor Xa may be evaluated inone or more of the following Enzyme Inhibition assays, or in otherstandard assays known to those skilled in the art.

Enzyme Inhibition Assay

Human factor Xa and human thrombin are purchased from Enzyme ResearchLaboratories (South Bend, Ind., USA). Other proteases are from othercommercial sources. Chromogenic para-nitroanilide peptide proteasesubstrates are purchased from Midwest Biotech (Fishers, Ind., USA).

The binding affinities for human factor Xa are were measured as apparentassociation constants (Kass) derived from protease inhibition kineticsas described previously.^(a,b,c,d) The apparent Kass values are obtainedusing automated (BioMek-1000) dilutions of inhibitors (Kassdeterminations are performed in triplicate at each of four-eightinhibitor concentrations) into 96-well plates and chromogenic substratehydrolysis rates determined at 405 nm using a Thermomax plate readerfrom Molecular Devices (San Francisco). For factor Xa inhibition, theassay protocol is: 50 μL buffer (0.06 M tris, 0.3 M NaCl, pH 7.4); 25 μLinhibitor test solution (in MeOH); 25 μL human factor Xa (32 nM in 0.03M tris, 0.15 M NaCl, 1 mg/mL HSA); finally, 150 μL BzIleGluGlyArgpNA(0.3 mM in water) added within 2 min to start hydrolysis. Final [factorXa] is 3.2 nM. [Free Xa] and [bound Xa] are determined from linearstandard curves on the same plate by use of SoftmaxPro software for eachinhibitor concentration and apparent Kass calculated for each inhibitorconcentration which produced hydrolysis inhibition between 20% and 80%of the control (3.2 nM factor Xa): apparent Kass[E:I]/[E_(f)][I_(f)]=[E_(b)]/[E_(f)][I^(o)-I_(b)]. The apparent Kassvalues so obtained are approximately the inverse of the Ki for therespective inhibitors [1/appKass=app Ki]. The variability of meanapparent Kass values determined at the single substrate concentration is+/−15%. The assay system Km was measured as 0.347+/−0.031 mM [n=4]; andVmax was 13.11+/−0.76 μM/min.

Kass values are determined with thrombin and other proteases using thesame protocol with the following enzyme and substrate concentrations:

-   thrombin, 5.9 nM with 0.2 mM BzPheValArgpNA;-   factor XIa, 1.2 nM with 0.4 mM pyroGluProArgpNA;-   factor XIIa, 10 nM with 0.2 mM HDProPheArgpNA;-   plasmin, 3.4 nM with 0.5 mM HDValLeuLyspNA;-   nt-PA, 1.2 nM with 0.8 mM HDIleProArgpNA;-   urokinase, 0.4 nM with 0.4 mM pyroGluGlyArgpNA;-   aPC, 3 nM with 0.174 mM pyroGluProArgpNA;-   plasma kallikrein, 1.9 nM with D-ProPheArgpNA; and-   bovine trypsin, 1.4 nM with 0.18 mM BzPheValArgpNA.    Citations-   (a) Sall D J, J A Bastian, S L Briggs, J A Buben, N Y Chirgadze, D K    Clawson, M L Denny, D D Giera, D S Gifford-Moore, R W Harper, K L    Hauser, V J Klimkowski, T J Kohn, H-S Lin, J R McCowan, A D    Palkowitz, G F Smith, M E Richett, K Takeuchi, K J Thrasher, J M    Tinsley, B G Utterback, S-CB Yan, M Zhang. Dibasic    Benzo[b]thiophenes Derivatives as a Novel Class of Active Site    Directed Thrombin Inhibitors. 1. Determination of the Serine    Protease Selectivity, Structure-Activity Relationships and Binding    Orientation. J Med Chem 40 3489-3493 (1997).-   (b) Smith G F, T J Craft, D S Gifford-Moore, W J Coffman, K D Kurz,    E Roberts, R T Shuman, G E Sandusky, N D Jones, N Chirgadze, and C V    Jackson. A Family of Arginal Thrombin Inhibitors Related to    Efegatran. Sem. Thrombos. Hemost. 22, 173-183 (1996).-   (c) Smith G F, D S Gifford-Moore, T J Craft, N Chirgadze, K J    Ruterbories, T D Lindstrom, J H Satterwhite. Efegatran: A New    Cardiovascular Anticoagulant. In New Anticoagulants for the    Cardiovascular Patient. Ed. R Pifarre. Hanley & Belfus, Inc.,    Philadelphia (1997) pp 265-300.-   (d) Sall D J, D L Bailey, J A Bastian, N Y Chirgadze, A C    Clemens-Smith, M L Denney, M J Fisher, D D Geira, D S Gifford-Moore,    R W Harper, L M Johnson, V J Klimkowski, T J Kohn, H S Lin, J R    McCowan, A D Palkowitz, M E Richett, G F Smith, D W Snyder, K    Takeuchi, J E Toth, M Zang. Diamino Benzo[b]thiophene Derivatives as    a Novel Class of Active Site Directed Thrombin Inhibitors: 5.    Potency, Efficacy and Pharmacokinetic Properties of Modified C-3    Side Chain Derivatives. J. Med. Chem., 43, 649-663 (2000).

The compounds of formula (I) exemplified herein have been found toexhibit a Kass of greater than 1×10⁶ L/mole in the enzyme inhibitionassay.

The ability of a test compound to elongate Partial Thromboplastin Time(Prothrombin Time) may be evaluated in the following test protocols.

Partial Thromboplastin Time (Prothrombin) Test Protocol

Venous blood is collected into 3.2% (0.109 M) trisodium citratevacutainer tubes at 1 volume of anticoagulant to nine volumes of blood.The blood cells are separated by centrifugation at 700 g for ten minutesto yield plasma, which is frozen at 70° C. until required.

To perform the test, 100 μL of plasma are pipetted into in a glass testtube, 1 μL of test compound in DMSO is added, and allowed to warm to 37°over two minutes. 100 μL of warm (37°) Manchester (tissue thromboplasin)reagent (Helena Biosciences, UK) is added, allowed to equilibrate fortwo minutes. 100 μL of warm (37°) 25 mM calcium chloride solution isadded to initiate clotting. The test tube is tilted three times througha 90° angle every five seconds to mix the reagents and the time to clotformation recorded. Data from a series of observations and test compoundconcentrations are analysed by a SAS statistical analysis program and aCT2 (Concentration required to double clotting time) for each compoundis generated.

The compounds of the invention have been found to significantly elongatethe partial thromboplastin time (Prothrombin time).

Alternative Prothrombin Time and APTT Protocols

Coagulation Determinations: Prothrombin Times and APTT values aredetermined in HUMAN PLASMA with a STA instrument (Stago). BioPT is aspecial non-plasma clotting assay triggered with human tissue factor(Innovin). Possible binding to albumen or to lipid are assessed bycomparing the BioPT effects in the presence/absence of 30 mg/mL humanalbumen (HSA) and 1 mg/mL phosphatidyl choline (PC). Inhibitors aredelivered in 50% aqueous methanol vehicle.

APTT Assay

-   75 μL plasma Citrol Baxter-Dade Citrated Normal-   Human Plasma-   25 μL test solution-   75 μL Actin Baxter-Dade Activated Cephaloplastin incubate 2 min min.    @ 37° C.-   75 μl CaCl₂ (0.02 M)    PT Assay-   75 μL plasma-   25 μL test solution-   75 μL saline incubate 1 min. @ 37° C.-   75 μL Innovin Baxter-Dade Recombinant Human Tissue Factor

Further advantageous properties of compounds of formula (I) may bedemonstrated by measuring their pharmacodynamic (PD) and pharmacokinetic(PK) properties in laboratory animal species such as rats and dogsfollowing oral dosing in the fasted and in the fed state.

1. A compound of formula (I)

in which:— R¹ represents pyrrolidin-1-yl, piperidin-1-yl or a group offormula

in which X represents CH or N; R² represents a hydrogen atom or a(1-6C)alkyl, (3-6C)cycloalkyl, fluoro(1-4C)alkyl, fluoro(2-4C)alkanoyl,hydroxy(2-4C)alkyl or pyridyl group; n represents 1, 2 or 3; Zrepresents CH₂, O or NR⁵, in which R⁵ represents a hydrogen atom or a(1-4C)alkyl group, provided that when R¹ represents pyrrolidin-1-yl,piperidin-1-yl or a group of formula

and Z represents O or NR⁵, then n represents 2 or 3; R³ represents:— (i)phenyl which is unsubstituted or substituted by methylenedioxy or by asubstituent selected from halogen, (1-4C)alkyl, hydroxy, (1-4C)alkoxy,trifluoromethyl, difluoromethoxy, trifluoromethoxy, (1-4C)alkylthio,(1-4C)alkylsulfinyl, (1-4C)alkylsulfonyl, carboxy, aminocarbonyl, amino,(2-4C)alkanoylamino, aminosulfonyl, (1-4C)alkylaminosulfonyl, nitro,phenyl, phenoxy, benzyloxy and pyridyl; (ii) pyridyl, pyrimidyl orpyridazinyl, which is unsubstituted or substituted by a halogen atom;(iii) furyl, thienyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, thiadiazolyl, each of which is unsubstituted or substitutedby (1-4C)alkyl or amino; (iv) naphthyl, benzofuryl, benzothienyl,quinolyl or isoquinolyl; (v) (3-6C)cycloalkyl; or (vi) (1-4C)alkyl,which is unsubstituted or substituted by hydroxy, (1-4C)alkoxy, phenoxy,carboxy, aminocarbonyl, aminosulfonyl, (1-4C)alkylthio, phenylthio,pyridylthio, amino, (1-4C)alkylamino, di(1-4C)alkylamino,piperidin-1-yl, morpholino, trifluoromethyl, phenyl, imidazolyl,pyridyl, (3-6C)cycloalkyl, oxa(4-6C)cycloalkyl, or aza(4-6C)cycloalkyl(which may bear an N-(1-4C)alkyl substituent); and R⁴ is selected from

in which X¹ represents a hydrogen atom, a halogen atom or an aminogroup; X² represents a hydrogen atom, a methyl group, a chlorine atom ora bromine atom; X³ represents a hydrogen atom, a methyl group or ahalogen atom; X⁴ represents a chlorine atom, a methoxy group or a methylgroup; and X⁵ represents a hydrogen atom, a halogen atom or a methylgroup; or a pharmaceutically acceptable salt thereof.
 2. A compound asclaimed in claim 1, in which R¹ represents a group of formula

in which X represents CH or N.
 3. A compound as claimed in claim 2, inwhich X represents CH.
 4. A compound as claimed in claim 2, in which R²represents a (1-6C)alkyl, (3-6C)cycloalkyl, fluoro(1-4C)alkyl,fluoro(2-4C)alkanoyl, hydroxy(2-4C)alkyl or pyridyl group.
 5. A compoundas claimed in claim 4, in which R² represents a methyl, ethyl,isopropyl, cyclopropyl, cyclopentyl, 2-fluoroethyl,2,2,2-trifluoroethyl, trifluoroacetyl, 2-hydroxyethyl or pyrid-4-ylgroup.
 6. A compound as claimed in claim 5, in which R² represents anisopropyl, cyclopropyl, cyclopentyl or pyrid-4-yl group.
 7. A compoundas claimed in claim 1, in which n represents 1 or
 2. 8. A compound asclaimed in claim 7, in which n represents
 1. 9. A compound as claimedclaim 1, in which Z represents CH₂.
 10. A compound as claimed in claim1, in which Z represents O.
 11. A compound as claimed in claim 1, inwhich Z represents NR⁵.
 12. A compound as claimed in claim 11, in whichR⁵ is hydrogen.
 13. A compound as claimed in claim 1, in which R³represents:— (i) phenyl, 2,3-methylenedioxyphenyl, 2-fluorophenyl,4-fluorophenyl, 2-chlorophenyl, 2-methylphenyl, 2-methoxyphenyl,2-trifluoromethylphenyl, 2-difluoromethoxyphenyl, 4-carboxyphenyl or4-aminocarbonylphenyl; (ii) pyrid-2-yl or pyrid-4-yl; (iii) fur-2-yl,fur-3-yl, thien-2-yl, thien-3-yl, imidazol-2-yl, thiazol-2-yl,thiazol-4-yl, 2-methylthiazol-4-yl or 2-aminothiazol-4-yl; (iv)naphth-1-yl, naphth-2-yl, benzofuryl, benzothienyl, quinolin-4-yl orquinolin-8-yl; (v) cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;or (vi) methyl, ethyl, propyl, isopropyl, butyl, 2-methylpropyl,hydroxymethyl, 1-hydroxyethyl, methoxymethyl, 1-methoxyethyl,methylthiomethyl, 2-methylthioethyl, prop-2-ylthiomethyl,N,N-dimethylaminomethyl, phenylthiomethyl, pyrid-2-ylthiomethyl,carboxymethyl, 2-carboxyethyl, aminocarbonylmethyl,2-aminocarbonylethyl, morpholinomethyl, 2,2,2-trifluoroethyl, benzyl,pyrid-2-ylmethyl, pyrid-3-ylmethyl, pyrid-4-ylmethyl,imidazol-1-ylmethyl, imidazol-4-ylmethyl, 3-methylimidazol-4-ylmethyl,cyclohexyl-4-ylmethyl, tetrahydropyran-4-ylmethyl, piperidin-1-ylmethylor 1-methylpiperidin-4-ylmethyl.
 14. A compound as claimed in claim 13,in which R³ represents phenyl, 2-fluorophenyl or 2-chlorophenyl.
 15. Acompound as claimed in claim 14, in which R³ represents phenyl. 16.(canceled)
 17. (canceled)
 18. A compound as claimed in claim 1, in whichR⁴ is 4-chlorophenyl, 4-methoxyphenyl, indol-6-yl, 3-methylindol-6-yl,3-chloroindol-6-yl, 5-chloroindol-2-yl or 6-chlorobenzo[b]thiophen-2-yl.19. A compound as claimed in claim 18, in which R⁴ is 4-methoxyphenyl,indol-6-yl or 5-chloroindol-2-yl.
 20. A pharmaceutical composition,which comprises a compound as claimed in claim 1, together with apharmaceutically acceptable diluent or carrier.
 21. A process forpreparing a compound as claimed in claim 1, which comprises (a) reactinga compound of formula (II)

or a salt thereof, with a compound of formula (III)HOOC—R⁴  (III) or a reactive derivative thereof; (b) for a compound offormula I in which R² represents a (1-6C)alkyl, (3-6C)cycloalkyl,fluoro(1-4C)alkyl, fluoro(2-4C)alkanoyl or hydroxy(2-4C)alkyl, reactinga corresponding compound of formula (I) in which R² represents ahydrogen atom, or a salt thereof, with an alkylating or acylating agent;(c) for a compound of formula (I) in which Z represents NH, deprotectinga compound of formula

in which R⁶ represents an amino protecting group; (d) for a compound offormula (I) in which R² represents a hydrogen atom, deprotecting acompound of formula (I) in which R² represents a protecting group;followed, if a pharmaceutically acceptable salt is desired, by forming apharmaceutically acceptable salt.
 22. A compound of formula (II)

or a salt thereof, in which R¹, n, Z and R³ are as defined in claim 1.23. A compound of formula (IV)

a salt thereof, in which R⁶ represents an amino protecting group, andR¹, R³ and R⁴ are as defined in claim
 1. 24. (canceled)
 25. (canceled)26. A method of treating a thrombotic disorder in a mammal requiringtreatment, which comprises administering an effective amount of acompound as claimed in claim 1.